UNIVERSIDADE DE LISBOA FACULDADE DE FARMÁCIA DEPARTAMENTO DE MICROBIOLOGIA E IMUNOLOGIA Mycobacterium tuberculosis host adaptation and evolution reflected by defense mechanisms against oxidative stress Olga Maria Elviro Mestre DOUTORAMENTO EM FARMÁCIA MICROBIOLOGIA 2012
156
Embed
Mycobacterium tuberculosis host adaptation and evolution … · Mycobacterium tuberculosis host adaptation and evolution reflected by defense mechanisms against oxidative stress Olga
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
UNIVERSIDADE DE LISBOA
FACULDADE DE FARMÁCIA
DEPARTAMENTO DE MICROBIOLOGIA E IMUNOLOGIA
Mycobacterium tuberculosis host adaptation and
evolution reflected by defense mechanisms
against oxidative stress
Olga Maria Elviro Mestre
DOUTORAMENTO EM FARMÁCIA
MICROBIOLOGIA
2012
UNIVERSIDADE DE LISBOA
FACULDADE DE FARMÁCIA
DEPARTAMENTO DE MICROBIOLOGIA E IMUNOLOGIA
Mycobacterium tuberculosis host adaptation and
evolution reflected by defense mechanisms
against oxidative stress
Olga Maria Elviro Mestre
Tese orientada pela Prof.ª Dr.ª Brigitte Gicquel e pela Prof.ª Dr.ª Madalena
Pimentel, especialmente elaborada para a obtenção do grau de doutor em
Farmácia (Microbiologia)
2012
The studies presented in this thesis were performed at Unité de Génétique Mycobacteriénne, Institut
Pasteur, Paris, under de supervision of Professor Brigitte Gicquel and Professor Madalena Pimentel.
Olga Maria Elviro Mestre was financially supported by a PhD fellowship (SFRH/BD/39079/2007) from
Fundação para a Ciência e Tecnologia (FCT), Lisboa, Portugal. The work presented in this thesis was
supported by the TB-ADAPT (LSHP-CT-2006-037919) project, funded by the European Commission
under the Health Cooperation Work Programme of the 6th Framework Programme, as well as by TB-VIR
(Grant agreement n° 200973) and NEWTBVAC (HEALTH-F3-2009-241745) projects, from the 7th
Framework Programme.
De acordo com o disposto no ponto 1 do artigo nº40 do regulamento de Estudos Pós-Graduados da
Universidade de Lisboa, deliberação nº 93/2006, publicado em Diário da Républica – II série nº 153 – 5
de Julho de 2003, a autora desta dissertação declara que participou na concepção e execução do
trabalho experimental, interpretação dos resultados obtidos e redacção dos manuscritos.
III
ABSTRACT
Part of the success of Mycobacterium tuberculosis lies in its ability to thrive inside macrophages,
where it is exposed to strong antimicrobials molecules, such as reactive oxygen species (ROS).
However, the role of defense mechanisms against ROS in M. tuberculosis pathogenesis remains
unclear. We used, for the first time, a functional genomic approach to investigate M. tuberculosis
responses against ROS. By screening a transposon mutant library we identified a high number of
mutants, with increased susceptibility to H2O2, in genes related to cell envelope functions, including
mmpL9. This revealed the importance of M. tuberculosis cell envelope against oxidative stress.
However, we have also identified genes implicated in other kind of defense mechanism against
ROS, such as moaD1. Infection of human macrophages has shown that both mmpL9 and moaD1
have a role in M. tuberculosis intracellular lifestyle, and previous studies suggested the same for
several other genes identified during our screening. Therefore, these represent potential virulence
factors useful for the development of future anti-tuberculosis strategies.
DNA repair, recombination and replication (3R) are important mechanisms in maintaining genome
stability by repairing DNA damages, such as those induced by ROS, however, variations on 3R genes
potentially increase genomic variability, due to an increase in mutation rates. Thus, analysis of
polymorphisms in 3R genes could indicate which strains are more prone to adapt and evolve. We
have analyzed polymorphisms in 3R genes in a collection of strains of a successful family of M.
tuberculosis strains, the Beijing/W family. Specific 3R polymorphisms were found to characterize
particular groups of Beijing/W strains for which a phylogeny was constructed. Certain groups were
found to be predominant, suggesting that strains of these genotypes might have some selective
advantage. Therefore, particular 3R SNPs may define pathogenic features that have contributed to
the evolution of the Beijing/W family.
Keywords: Mycobacterium tuberculosis, Reactive oxygen species, macrophage, DNA repair
recombination and replication, The Beijing/W family, Polymorphisms
IV
V
RESUMO
Mycobacterium tuberculosis, a bactéria responsável pela tuberculose, infecta cerca de 1/3 da
população mundial e é responsável pela morte de aproximadamente 1,5 milhões de pessoas por
ano. Estes números podem ser explicados, em parte, pela capacidade desta bactéria persistir no
interior de macrófagos, num ambiente extremamente agressivo, no qual é exposta a diferentes
moléculas antimicrobianas tais como as espécies reactivas de oxigénio. Estas, sendo altamente
reativas, causam danos em todo o tipo de moléculas incluindo lípidos, proteínas e DNA. Desta
forma, os mecanismos de defesa utilizados pelo M. tuberculosis contra as espécies reativas de
oxigénio são sem dúvida importantes para este, porém, o seu papel na virulência e patogénese
desta bactéria ainda é pouco claro.
O trabalho desenvolvido nesta tese consistiu na investigação dos mecanismos de defesa
utilizados pelo M. tuberculosis contra as espécies reactivas de oxigénio. Com este objectivo,
realizou-se pela primeira vez, um screening de uma biblioteca de mutantes construída por
transposição, na estirpe clinica da família Beijing/W - GC1237, de forma a selecionar mutantes
sensíveis a espécies reativas de oxigénio. A análise de cerca de 6000 mutantes permitiu a selecção
de 18, sensíveis a peróxido de hidrogénio, para os quais a amplificação e posterior sequenciação do
sítio de inserção do transposão levaram à identificação de 11 genes. Verificou-se que grande parte
dos genes apresenta funções associadas ao invólucro celular bacteriano, o que revela que o
invólucro do M. tuberculosis representa a primeira barreira de defesa contra as espécies reactivas
de oxigénio nesta bactéria. O gene mmpL9 foi um dos identificados, cuja proteína se encontra
possivelmente envolvida no transporte de lípidos para o invólucro celular. Curiosamente, três
mutantes com diferentes mutações neste gene foram seleccionados. Identificaram-se também
alguns genes envolvidos noutro tipo de mecanismos tais como, moaD1, envolvido na síntese do
cofactor molibdénio.
Uma vez que o M. tuberculosis tem de fazer face às espécies reativas de oxigénio no interior de
macrófagos, o passo seguinte consistiu em analisar o fenótipo de alguns destes mutantes nestas
células. Para o efeito, macrófagos humanos foram infectados com um dos mutantes no gene
mmpL9 ou com o mutante no gene moaD1, uma vez que estudos anteriores demonstraram o papel
de diferentes MmpLs na virulência desta bactéria e que outros genes envolvidos na síntese do
cofactor molibdénio são importantes para a sobrevivência do M. tuberculosis no interior de
macrófagos. Em ambos os casos observou-se uma diminuição na capacidade de crescimento destas
VI
estirpes no interior destas células, em comparação com a estirpe selvagem. A complementação
destas estirpes mutantes restaurou o fenótipo da estirpe selvagem, o que demonstra o papel
destes genes no crescimento de M. tuberculosis em macrófagos humanos. Porém, a
complementação restaurou apenas parcialmente a sensibilidade destes mutantes às espécies
reactivas de oxigénio in vitro, em comparação com a estirpe selvagem. No entanto, mmpL9 e
moaD1 deverão ter um papel na resposta às espécies reativas de oxigénio em M. tuberculosis, caso
contrário, a complementação não teria restaurado de todo o fenótipo selvagem, nas condições
referidas.
A comparação da sequência do gene mmpL9 da nossa estirpe selvagem, GC1237, com a estirpe
de referência laboratorial, H37Rv, revelou a presença de uma deleção de um nucleótido na posição
218. Contudo, os nossos resultados obtidos a partir da infecção de macrófagos com o mutante
mmpL9 e com a mesma estirpe após complementação da mutação sugerem que o gene mmpL9
deverá ser expresso apesar desta deleção. É possível que ocorra uma reniniação da tradução a
partir de um codão de iniciação situado a montante da deleção, na posição 258, no gene mmpL9.
Para além disso, a complementação do nosso mutante mmpL9 com o respectivo gene da estirpe
H37Rv, restaurou apenas parcialmente o fenótipo da estirpe selvagem, GC1237, durante a infecção
de macrófagos. Estas observações sugerem que a proteína MmpL9 na estirpe GC1237 poderá ser
diferente da existente na estirpe H37Rv. A análise da sequência de todos os genes mmpL existentes
no genoma de M. tuberculosis, numa coleção de estirpes que representam diferentes famílias,
sugeriu que a deleção identificada poderá realmente ter um efeito na proteína. Verificou-se ainda
que esta deleção é aparentemente específica para todas as estirpes modernas da família Beijing.
Isto indica que a deleção do nucleótido 218 poderá ter conferido alguma vantagem selectiva a
estas estirpes que contribuiu para a sua evolução.
Para além de moaD1 e mmpL9, alguns dos outros genes identificados durante o screening como
importantes para a resposta de M. tuberculosis às espécies reativas de oxigénio, foram igualmente
descritos, em estudos anteriores, como importantes para a capacidade desta bactéria sobreviver
intracelularmente. Isto indica uma correlação entre sensibilidade ao stress oxidativo e capacidade
de sobreviver ou replicar-se no interior de macrófagos. No entanto, a infecção de macrófagos
tratados com inibidores da NADPH oxidase, a enzima que produz as espécies reativas de oxigénio
nestas células, com os mutantes nos genes mmpL9 e moaD1, não permitiu confirmar esta hipótese.
É possível que estes mutantes sejam sensíveis a outras moléculas antimicrobianas encontradas no
interior do macrófago, tais como as espécies reativas de azoto, que, em conjunto com as espécies
VII
reativas de oxigénio, são responsáveis pelo crescimento atenuado observado em macrófagos. Em
conclusão, este trabalho permitiu a identificação de genes envolvidos na defesa do M. tuberculosis
contra as espécies reactivas de oxigénio, os quais aparentam ter igualmente um papel na
sobrevivência desta bactéria nas suas células hospedeiras, os macrófagos. Estes genes representam
potenciais factores de virulência que poderão ser úteis para o desenvolvimento de futuros
antibióticos ou vacinas.
Numa segunda parte desta tese, realizou-se uma análise dos polimorfismos existentes em genes
de reparação, recombinação e replicação (3R) de DNA numa família específica de estirpes de M.
tuberculosis, a família Beijing. Os mecanismos de reparação, recombinação e replicação são
extremamente importantes na manutenção da estabilidade genómica, através da reparação de
danos causados no DNA, tais como os induzidos pelas espécies reativas de oxigénio. Por outro lado,
estes mecanismos podem ser igualmente responsáveis pela introdução de variabilidade genética.
Polimorfismos nos genes que codificam para as proteínas envolvidas nestes mecanismos poderão
induzir um aumento na taxa de mutação, e consequentemente, a acumulação de mutações
vantajosas para as estirpes, como por exemplo, mutações responsáveis pela resistência a
antibióticos. Deste modo, a análise de polimorfismos nos genes 3R poderá indicar que estirpes
estão mais predispostas a adaptar-se ou evoluir. A família Beijing é uma família de M. tuberculosis
que apresenta uma maior virulência e que tem sido identificada um pouco por todo o mundo como
estando frequentemente associada a resistência a antibióticos. Deste modo, analisaram-se
polimorfismos em genes 3R numa coleção de estirpes Beijing, isoladas em várias partes do mundo.
Diferentes polimorfismos foram identificados que permitiram a discriminação de vários grupos,
para os quais foi construída uma árvore filogenética. Estes resultados foram congruentes com os
resultados obtidos utilizando outros marcadores genéticos, o que significa que as mesmas
associações filogenéticas foram obtidas, para a colecção de estirpes utilizada neste estudo, usando
polimorfismos nos genes 3R ou outro tipo de marcadores genéticos.
Uma grande percentagem das estirpes foi agrupada num dos grupos, Bmyc10, que incluiu
estirpes isoladas em diferentes partes do mundo. Um estudo anterior demonstrou que estirpes
com características genéticas que definem as deste grupo são igualmente predominantes numa
outra região geográfica, não representada no nosso estudo. Em conjunto, estes resultados
sugerem que o genótipo das estirpes do grupo Bmyc10 poderá ter-lhes conferido alguma
vantagem selectiva que permitiu a sua evolução. Isto é igualmente sugerido num estudo anterior,
no qual a caracterização do efeito da mutação no gene mutT2, que caracteriza todas as estirpes do
VIII
grupo Bmyc10, indica que esta induz uma alteração na função da proteína que pode ser vantajosa
para as estirpes que a possuem. Portanto, alguns dos polimorfismos identificados no nosso estudo
poderão ter um efeito na função das respectivas proteínas, o que significa que este tipo de análise
é importante para compreender o significado dos mesmos.
Em conclusão, a análise de polimorfismos em genes 3R demonstrou que diferentes grupos
podem ser identificados na família Beijing caracterizados por polimorfismos específicos. Estes
podem ter conferido alguma vantagem que permitiu a expansão de certos grupos e contribuiu para
a evolução desta família. A análise da variabilidade genética entre estirpes é importante uma vez
que estas podem reflectir diferenças patogénicas. Este estudo poderá contribuir para aprofundar
os nossos conhecimentos acerca dos mecanismos que determinam o êxito das estirpes da família
Beijing.
Palavras-Chave: Mycobacterium tuberculosis; Espécies reactivas de oxigénio; Macrófago;
Reparação, recombinação e replicação de ADN; Família Beijing; Polimorfismos
IX
ACKNOWLEDGMENTS
I would like to thank, first of all, to my supervisor, Professor Brigitte Gicquel, for accepting me in her
laboratory, and for all the support, help and guidance during the last six years. Thank you for believing
in me and for giving the opportunity to learn all the things I have learnt that allowed me to evolve
professionally and personally and became the person I am today. Pour tout ça, un grand Merci.
Queria agradecer igualmente à Professora Madalena Pimentel, co-orientadora desta tese. Agradeço
todo o apoio que me deu durante estes cinco anos em que, esteve sempre disponível para nos
reunirmos e discutirmos sobre a evolução dos trabalhos, e para me ajudar e aconselhar. Obrigada pela
sua ajuda e apoio, principalmente nesta fase final, foi muito importante para mim.
Ao Tiago, por ter acreditado em mim e me ter apoiado incondicionalmente. Sem ti este trabalho nunca
teria sido possível. Obrigada por todo o apoio e carinho, que tu e a Zrinka sempre me deram. Por me
teres ouvido e aconselhado e por me teres orientado e guiado. Vou estar eternamente agradecida por
tudo.
À Helena, a minha grande amiga, a quem dificilmente conseguirei exprimir o quanto estou agradecida.
Pelo apoio incondicional e pela paciência que tiveste, sobretudo nos momentos mais difíceis. Obrigada
por todos os momentos únicos e inesquecíveis que passámos juntas no laboratório e em Paris!
Obrigada pela amizade, que vai para sempre durar, não tenho dúvidas.
À Mena, amiga do coração, foste um apoio imprescindível neste cinco anos. Este percurso não teria
sido possível se não tivesses estado presente para me ajudares, escutares e aconselhares. Por isso,
muito obrigada a ti, ao Elias, e ao Sebastian por tornarem a minha estadia em Paris mais fácil e por me
proporcionarem momentos únicos e especiais.
À Soraia pela amizade e por teres estado sempre presente e disponível para me apoiares apesar da
distância, e sobretudo pela ajuda e apoio nesta fase final, muito obrigada por tudo amiga.
Ao Bruno e à Elisabete, que estiveram sempre disponíveis para me apoiar, obrigada! Ao Hugo, muito
obrigada pela constante preocupação e apoio. Obrigada aos três pelos momentos inesquecíveis
passados juntos em Paris, nunca esquecerei!
Ao Amine, merci beaucoup pour tous les moments passés ensemble au labo, pour travailler et aussi
pour décontracter et rigoler. Pour toute ton aide et soutien et aussi pour ta patience, essentiel pendant
ces dernières années, je te remercie vraiment du fond du cœur.
X
À Raquel, por todas as horas passadas no P3, foste uma ajuda importante, obrigada, pelo apoio e pela
preocupação e carinho que tu e Marco me deram.
À tous les personnes avec qui j’ai travaillé au laboratoire à l’Institut Pasteur, en particulier à Sandrine et
Véronique, pour toute votre aide, soutient et compagnie, pour les bons moments passés ensemble, je
vous remercie et je m’en souviendrais toujours!
A special thanks to Alessandro for all the advices, support, discussions, and long hours spent in the P3,
and off course for the Italian meals in the weekends!
A todos os meus amigos, em especial à Telma que sempre se preocupou e sempre me apoiou, obrigada
pela tua amizade incondicional.
À minha família, primos, tios e avós muito obrigada pela constante preocupação e apoio!
Aos meus pais, pelo amor e apoio incondicional que sempre me deram, sem eles sem dúvida alguma
que eu não teria conseguido chegar até aqui e ser o que sou hoje. Por tudo isso e pela preocupação e
ajuda, não tenho palavras que possam agradecer tudo o que já fizeram por mim, a não ser dizer que vos
adoro e que tenho muito orgulho em ser vossa filha.
À minha irmã e ao meu cunhado, e claro, às minhas sobrinhas lindas, pelo amor que me dão e por todo
o apoio que me deram ao longo destes anos, sobretudo pela paciência nesta fase final. A vossa ajuda
foi imprescindível para finalizar esta tese, muito muito obrigada, adoro-vos!
Ao meu irmão e cunhada obrigada pelo carinho, apoio e preocupação incondicional, muito obrigada!
Aos meus sogros, ao Nuno e à Inês, por me tratarem de uma forma tão especial, por se preocuparem
comigo e pelo apoio e força que sempre me deram, obrigada.
Por fim, ao Rui, pelo teu amor, apoio, ajuda, compreensão e sobretudo pela enorme paciência que
tiveste durante estes cinco anos. Sem ti seguramente eu não teria tido a força que tive para concluir
esta tese. Obrigada por tudo e por fazeres parte da minha vida. Por tudo isto e muito mais estarás
sempre no meu coração.
XI
ABREVIATIONS
3R DNA repair, recombination and replication 8-oxoG 7,8-dihydro-8-oxo-2'-deoxyguanosine
wild-type (GC1237) strains was determined by comparing bacteria treated with 9mM of hydrogen
peroxide to untreated controls. Data and error bars represent means and standard deviations of the
results from triplicates in a representative experiment carried out three times with similar results.
Statistically significant differences were calculated using the Student’s two-tailed, unpaired, t-test, and
are indicated by asterisks *P<0,05; ***P<0,001; ****P<0,0001.
The difference in sensitivity to H2O2 between the ppe54 mutant and the wild-type strain was not
statistically significant. This suggests that the effect of H2O2 on this strain is not bactericidal but
probably only bacteriostatic as we observed growth inhibition in the presence of H2O2 during the
screen (Table 2). Additionally, two different mutants, carrying independent transposon insertions
66 Chapter 2
in the ppe54 gene, were selected (Table 2), confirming the sensitivity to oxidative stress of any
strain carrying a mutation in this gene.
2.4.4 MmpL9 and MoaD1 are important for M. tuberculosis survival in human
macrophages
Because bacteria have to face oxidative stress conditions inside host cells we decided to analyze
growth in human macrophages of the moaD1 and mmpL9 mutants which were the most sensitive
strains to killing by H2O2 (Figure 3). Additionally, MmpLs have been identified as important
determinants of M. tuberculosis virulence (Camacho et al., 1999; Converse et al., 2003; Cox et al.,
1999; Domenech et al., 2005), even though reports regarding mmpL9 mutant phenotype in mice
are contradictory (Cox et al., 1999; Domenech et al., 2005; Lamichhane et al., 2005; MacGurn and
Cox, 2007). Genes involved in the same biosynthetic pathway as moaD1 have been previously
shown to be important for bacterial intracellular lifestyle (Rosas-Magallanes et al., 2007),
suggesting an important role for MoCo in M. tuberculosis survival inside host cells.
Monocyte-derived macrophages were infected with mutant, wild-type and complemented
strains and after six days post-infection cells were lysed and bacteria were plated to analyze CFUs.
As shown in Figure 4, both moaD1 and mmpL9 (100D7) mutants displayed an impaired intracellular
growth when compared to their wild-type counterpart (Figure 4A and B). At day 6 post-infection,
the moaD1 mutant showed a 4-fold increase in intracellular growth while the wild-type showed a
12-fold increase, with respect to time-point zero. Complementation of the moaD1 mutant using an
integrative vector restored the wild-type phenotype inside macrophages (Figure 4A). These results
suggest that MoCo might be indeed important for mycobacterial growth inside host cells.
Infection of human macrophages with the mmpL9 mutant resulted in an increase of 2.5-fold
while the wild-type had a 15-fold increase in CFUs, after 6 days (Figure 4B). Sequence analysis of
the mmpL9 gene of the wild-type strain GC1237 revealed, when compared to H37Rv, the presence
of one nucleotide deletion at position 218. To better understand the possible effects of this
frameshift mutation, we decided to complement the mmpL9 mutant with mmpL9 of either GC1237
or H37Rv. As shown in Figure 4B, complementation restored the wild-type phenotype inside
macrophages using mmpL9 of GC1237. However, it seems to be only partially restored when
complemented with H37Rv mmpL9.
67 M. tuberculosis resistance to ROS
Figure 4. Intracellular growth of mmpL9 and moaD1 mutants in human macrophages. Monocyte-
derived macrophages where infected with wild-type, moaD1 (A) or mmpL9 (B) mutant and
complemented (COMP) strains, at an MOI of 1:100 (bacteria per macrophage). At time point zero (0)
and six days of infection, cells were lysed and bacteria were enumerated. Data and error bars represent
means and standard deviations of the results from triplicates in a representative experiment carried out
three times with similar results. Statistically significant differences were calculated using the Student’s
two-tailed, unpaired, t-test, and are indicated by asterisks *P<0,05; **P<0,01;***P<0,001.
Unfortunately, we could not detect, using Western blotting, expression of either H37Rv or
GC1237 mmpL9 carrying a hemagglutinin tag, under the control of its own or of a strong promoter
(hsp60), in either M. tuberculosis or M. smegmatis, using different growth conditions and whole
cell lysate preparation methods (data not shown).
2.4.5 The mmpL9 deletion at position 218 is conserved in Beijing/W strains
To investigate the possible effects of the deletion identified in mmpL9 for the GC1237 strain, we
searched for SNPs in the 13 M. tuberculosis mmpL genes (Cole et al., 1998) in a collection of strains
representing main M. tuberculosis lineages. Statistical analysis of the identified SNPs suggests that
68 Chapter 2
the mmpL9 gene does not accumulate more polymorphisms than the other mmpLs (Table 3),
excluding the hypothesis of pseudogene formation but not that of an effect, of the observed
polymorphisms, on protein’s functions.
Table 3. Statistical analysis of SNP density in mmpL genes in a collection of M. tuberculosis genomes.
Name Length (bp)
SNPs Binomial testa
Bonferroni correctionb
mmpL1 2877 3 0,926187042 12,96661859
mmpL2 2907 9 0,167599855 2,346397974
mmpL3 2835 13 0,008366836 0,117135699
mmpL4 2904 6 0,565387826 7,915429562
mmpL5 2895 7 0,406734347 5,694280858
mmpL6 1194 6 0,026461116 0,370455623
mmpL7 2763 5 0,670824515 9,391543207
mmpL8 3270 9 0,270440559 3,786167821
mmpL9 2889 7 0,404469247 5,662569455
mmpL10 3009 2 0,980458231 13,72641523
mmpL11 2901 5 0,716449242 10,03028939
mmpL12 3441 11 0,128927703 1,804987847
mmpL13a 912 4 0,071781264 1,004937698
mmpL13b 1413 1 0,862276271 12,07186779
Total 36210 88
aThe binomial test was used to identify mmpL genes that accumulate more SNPs than expected. The p-value was
calculated according to the number of SNPs and length of each gene and the total number of SNPs and genes length. bThe final p-value was estimated after Bonferroni correction.
Additionally, analysis of polymorphisms in mmpL9 in these collection of strains have shown that
the deletion in nucleotide 218 is specific to all modern and ancestral Beijing/W strains, being
absent from early ancestral Beijing/W strains, such as 94_M4241A, and strains of any other M.
tuberculosis family/lineage (Figure 5).
69 M. tuberculosis resistance to ROS
Figure 5. Graphical representation of the distribution of polymorphisms in mmpL9 in several M.
tuberculosis genomes. Polymorphisms in mmpL9 were analyzed in 24 different M. tuberculosis
genomes (Namouchi et al., 2012) that correspond to the following groups/lineages according to
node (2); Bmyc10 node (188). Table A1 describes the strains that belong to each node. Mv represents a
median vector created by the software and can be interpreted as possibly extant unsampled sequences
or extinct ancestral sequences. The relative proportion of isolates in each node, of a given geographic
origin, may not reflect the population structure of the Beijing/W family of that geographic region.
98 Chapter 3
99 Polymorphisms in 3R genes in Beijing/W strains
DISCUSSION 3.5
M. tuberculosis complex strains have been considered as highly clonal, when compared to other
pathogens (Achtman, 2008). Initial reports have even suggested that these strains share 99%
similarity at the nucleotide level (Sreevatsan et al., 1997). However, in the recent years, large
numbers of SNPs have been identified and used in order to get a more detailed insight into the
diversity and evolutionary history of this bacteria (Baker et al., 2004; Dos Vultos et al., 2008; Filliol
et al., 2006; Hershberg et al., 2008). SNPs analysis is a simple and relatively fast way to compare
organisms and trace back the evolutionary history of strains, as some SNPs are highly informative.
Therefore, SNPs analyses are becoming more and more attractive with the increasing number of
genome sequencing projects. This will provide data particularly relevant to understand the genetic
basis for strain differences in pathogenesis.
Allelic variation in 3R genes seems to be an important mechanism in evolution and adaptation
of microorganisms. Defective 3R systems could potentially increase genomic variability, due to an
increase in mutation rates. Strains with high mutations rates (mutators), may have, in certain
conditions, a selective advantage, as they produce more adaptive mutations (Denamur and Matic,
2006; Taddei et al., 1997; Tonjum and Seeberg, 2001). The Beijing/W family is a group of strains
that seems to have a selective advantage when compared to other M. tuberculosis families.
Therefore, polymorphisms in 3R genes were analyzed in a collection of Beijing/W isolates from
different geographic origins. SNPs in 3R genes associated with the Beijing/W family were identified
that enabled the discrimination of 26 different sequence types for which a phylogeny was
constructed. Phylogenetic relationships established by sequence types were in agreement with
evolutionary pathways suggested by other genetic markers, such as Large Sequence
Polymorphisms (LSPs). The remarkable clonality of M. tuberculosis implies that different genetic
markers reveal similar phylogenies (Supply et al., 2003), if not, these are not robust markers
appropriate to evolutionary analyses.
Polymorphisms in 3R genes show that the Beijing/W family can be subdivided in different
groups, as previously shown using other genetic markers (Hanekom et al., 2007; Tsolaki et al.,
2005). We did find however, a recently expanded group, Bmyc10, which seems to be predominant
as it includes over 60% of strains. This sequence type was identified in isolates from China, where
the Beijing/W family is highly prevalent, but also in other countries, where the Beijing/W family is
less prevalent, such as Madagascar and The Netherlands. In a previous study, a group of Beijing/W
strains characterized by the RD181 deletion and polymorphisms in mutT4 and mutT2 appears to be
predominant in a collection of strains isolated in Italy (Rindi et al., 2009). Strains belonging to
100 Chapter 3
Bmyc10 node also had the RD181 deletion and the same SNPs in mutT4 and mutT2 genes (SNP6
and SNP12). This seems, though, to be a prevalent group in different parts of the world, suggesting
that Beijing/W strains of this genotype might have some selective advantage. The Bmyc25 group
that includes the Gran Canaria TB outbreak strain GC 1237 (Caminero et al., 2001), might represent
another predominant group among Beijing/W strains. Taken together, these observations suggest
that polymorphisms in 3R genes may confer advantageous phenotypes on certain Beijing/W
genotypes. Indeed, different Beijing/W strains show different pathogenic characteristics in human
macrophages (Theus et al., 2007), as well as in mice (Aguilar et al., 2010; Dormans et al., 2004), or
guinea pigs (Kato-Maeda et al., 2011; Palanisamy et al., 2009). However, host cell transcriptome
responses were found to be similar in Beijing/W strains from different genotypes defined by 3R
SNPs (Wu et al., 2012). Similarly, different Beijing/W genotypes, including Bmyc10 and Bmyc25
strains, do not seem to induce a differential cytokine modulation in macrophages (Wang et al.,
2010). Therefore, other pathogenic characteristics might explain the increased adaptability of
strains with the Bmyc10 and Bmyc25 genotypes (Wang et al., 2010; Wu et al., 2012). For example,
Beijing/W strains belonging to different sublineages defined by LSPs (Tsolaki et al., 2005) seem to
present differences in transmissibility in a mouse model of infection (Aguilar et al., 2010).
Beijing/W strains have also shown variability in the expression levels of the dormancy regulon
(DosR) (Fallow et al., 2010). Therefore, it could be interesting to evaluate differences in Beijing/W
strains ability to persist in a dormant state inside host cells. It should also be interesting to analyze
if these strains have different capacity to resist macrophage antimicrobial mechanisms during
hypoxia, a granuloma characteristic condition that determines DosR activation in M. tuberculosis
(Nickel et al., 2012). Hypoxia doesn’t change cytokine release but triggers an antimicrobial pathway
associated with growth inhibition of the bacilli (Nickel et al., 2012).
Analysis of the effect on enzyme characteristics of the variation in the mutT2 gene, a
characteristic of all Bmyc10 isolates (SNP12, Figure 2), has revealed significant changes in enzyme
properties, caused by a single amino acid substitution, that leads to protein destabilization. It was
suggested that this altered MutT2 enzyme may contribute to the success of strains due to an
increase in nucleotide-dependent reactions (Moreland et al., 2009). Therefore, some of the SNPs
identified in this study might have an effect on protein’s function. The analysis of the functional
effects of the polymorphisms observed in 3R genes might be crucial to understand the real
meaning of such variations. In our previous analysis we have shown that the observed variations in
3R might be slightly deleterious, resulting in suboptimal 3R system activity (Dos Vultos et al., 2008).
Therefore, some of these strains might have a mutator phenotype, increasing the probability of
acquiring mutations in genes conferring some selective advantage. For example, mutator strains
101 Polymorphisms in 3R genes in Beijing/W strains
may generate mutations that confer antibiotic-resistance at a higher rate than non-mutator strains
(Denamur and Matic, 2006). When antibiotic-resistance is mainly determined by the acquisition of
mutations in the chromosome, as is the case of M. tuberculosis (Heym et al., 1994), the advantage
of being a mutator increases significantly (Tenaillon et al., 1999). A study tried to evaluate
contribution of polymorphism on the DNA repair genes, mutT, to resistance to antibiotics. Even
though no statistically significant association of missense mutations on these genes with and
increased prevalence of antibiotic-resistance was detected, the authors couldn’t rule out the
hypothesis that mutator phenotypes might increase the rate of drug resistance (Lari et al., 2006).
Beijing/W strains have been often associated with drug resistance, even though, the underlying
mechanisms for this association remain unknown (Tuberculosis, 2006). Beijing/W strains have
shown similar rates of mutation-conferring resistance to rifampin compared to non-Beijing strains
(Werngren and Hoffner, 2003). Therefore, another explanation would be that drug-resistance in
Beijing/W strains has a lower or no cost on fitness, given that resistance-conferring mutations are
often associated with a fitness cost (Andersson and Levin, 1999). The fitness of non-Beijing drug
resistant strains was found to be slightly reduced when compared to drug-susceptible M.
tuberculosis. However, drug resistant Beijing/W strains presented some variability: some strains
showed loss of fitness while others did not (Toungoussova et al., 2004). Given that the fitness
impact of resistance-conferring mutations in M. tuberculosis depends on the genetic background of
the strain (Fenner et al., 2012; Gagneux et al., 2006b), the fitness cost of these mutations may vary
among different Beijing/W sublineages. Indeed, different sublineages of the Beijing/W family may
differ in their mechanisms of adaptation to drug selection pressures (Iwamoto et al., 2008;
Mokrousov et al., 2006). It is also possible that the accumulation of compensatory mutations will
mitigate the biological cost of drug-resistance mutations (Gagneux et al., 2006b). Thus, certain
Beijing/W sublineages could have an advantage due to the occurrence of compensatory mutations.
In mutator strains, the probability for this to occur is much higher. However, the concept of a
mutator phenotype in Beijing/W strains was not supported when the frequency of spontaneous
mutations was calculated using the Luria–Delbruck fluctuation test. The rate of spontaneous
mutations was the same in Beijing/W, non-Beijing and laboratory strains (Werngren and Hoffner,
2003). In mutator strains, reduction in mutation rates should occur, for example, by the acquisition
of suppressor/compensatory mutations, before the load of deleterious mutations becomes too
high (Denamur and Matic, 2006; Taddei et al., 1997). Thus, polymorphisms found in 3R genes may
be related to transient mutator phenotypes in Beijing/W strains.
In conclusion, analysis of polymorphisms in 3R genes has shown that different Beijing/W groups
can be identified and characterized by specific 3R SNPs. These might have induced some selective
102 Chapter 3
advantage that allowed the expansion of certain genotypes, therefore contributing to the evolution
of the Beijing/W family. We hope that our study will contribute to better understand the molecular
basis for the enhanced pathogenicity attributed to the Beijing/W family.
CHAPTER 4
Concluding Remarks
104 Chapter 4
105 Concluding Remarks
Mycobacterium tuberculosis is one of the most successful pathogens, being extremely adapted
to its host. It is estimated that one-third of the world’s population is infected with this pathogen
(WHO at www.who.int/topic/tuberculosis/en/) and, even though in 90-95% of these cases the
infection is contained, M. tuberculosis is not eliminated and is able to persist in its host for years,
until, disease develops due to not always well-understood reasons (Kaufmann and McMichael,
2005). Understanding the mechanisms used by M. tuberculosis to successfully persist in its host,
particularly inside macrophages, will lead to insights into possible targets for new effective anti-TB
strategies.
M. tuberculosis cell envelope constitution explains part of its resistance against host
antimicrobial mechanisms. It forms a permeability barrier and is, thus, the first line of defense
against toxic molecules (Brennan and Nikaido, 1995). However, the contribution of M. tuberculosis
envelope components to this remains poorly documented. We have shown, by screening, for the
first time, a transposon mutant library for mutants with increased susceptibility to reactive oxygen
species (ROS), that M. tuberculosis cell envelope is the first line of defense against ROS,
antimicrobial molecules produced by macrophages to destroy intracellular pathogens such as M.
tuberculosis (Flannagan et al., 2009). Certain cell wall lipids, such as LAM, have been previously
identified as ROS scavengers (Chan et al., 1991). Even though we did not identify any known genes
involved in the biosynthesis of mycobacterial lipids, such as pks (polyketide synthases), we have
identified transporters possibly involved in transport of lipids or other molecules to the cell
envelop (MmpL9 and Rv0986). We have identified as well, proteins that seem to be involved in the
synthesis of components of the cell envelope, although no known function has been assigned so
far (Rv1507c, Rv1508a, Rv1509, Rv3594). Several PPE coding genes were also identified. However,
how these proteins protect mycobacteria against ROS is not clear once not much is known about
the molecular function of PE/PPEs (Akhter et al., 2012). Nonetheless, PE_PGRS11 was shown to be
exposed to the cell surface and to be involved in mycobacterial resistance against H2O2-induced
oxidative stress. This protein was found to be a phosphoglycerate mutase, a protein involved in
glycolysis that has been previously demonstrated to decrease the accumulation of ROS in cells
(Chaturvedi et al., 2010). In addition, a transcriptomic analysis has also shown that several PE/PPE
genes are induced by H2O2, but not by NO, in M. tuberculosis (Voskuil et al., 2011). These results
provide proof that PE/PPEs have indeed a role in protecting mycobacteria against oxidative stress.
The highly impermeable cell wall of M. tuberculosis also contributes to its intrinsic resistance
against chemotherapeutic agents (Jarlier and Nikaido, 1994; Nikaido, 2001). Therefore, cell wall
components are good targets for developing new chemotherapeutic agents against TB. Indeed,
these are currently the target of several antimycobacterial agents, including the two important first
106 Chapter 4
line drugs, isoniazid and ethambutol (Sarkar and Suresh, 2011). Nonetheless, there is an ongoing
search for new cell wall targets. Certain bacterial antibiotics are responsible for an increase in ROS
production within cells via the fenton reaction (Kohanski et al., 2007). Tolerance to these
antibiotics may, therefore, depend on the ability of the cell to defend itself against ROS. Thus,
targeting molecules involved in resistance to ROS, such as those identified in our study, could
enhance the efficacy of mycobacterial drugs known to generate ROS, such as isoniazid, kanamycin
or ofloxacin (Kohanski et al., 2007; Mukherjee et al., 2009). Indeed, a mutant overexpressing
Wag31, a protein involved in regulation of polar cell wall synthesis, had increased susceptibility to
hydrogen peroxide as well as to isoniazid and ofloxacin (Mukherjee et al., 2009). This kind of
approach could significantly contribute to TB treatment accomplishment. On the other hand, it
could also avoid the appearance of drug-resistant bacteria. It was shown recently that bacterial
death induced by ROS might eliminate persisters (Grant et al., 2012), small populations that resist
to high doses of antibiotics and contribute to the rise in MDR- and XDR-TB (Keren et al., 2011).
Furthermore, these drug-tolerant, persistent bacteria have, in M. tuberculosis, the physiological
state of dormant bacilli, typically found in latent TB (Keren et al., 2011; Ulrichs and Kaufmann,
2006). Therefore, targeting M. tuberculosis molecules involved in resistance to ROS may contribute
to TB treatment improvement and could be suitable to treat patients latently infected with M.
tuberculosis, which represent today a huge reservoir for the disease, without increasing the burden
of drug-resistant TB.
Usually, basal oxidative defences are sufficient to protect bacteria from endogenous ROS that
result from aerobic respiration. However, these defences are inadequate if rates of ROS are
accelerated, for example during the phagocytic oxidative burst. Most microbes induce additional
responses when this happens (Imlay, 2008; Storz and Imlay, 1999). Thus, it is important to
discriminate the effects of phagocytic and endogenous ROS (Craig and Slauch, 2009; Storz and
Imlay, 1999). The fact that most of the genes identified in our study are components of the cell
envelop suggests that these are relevant to counteract ROS generated exogenously, such as those
originated during the phagocytic burst. However, extracellular ROS that penetrate bacterial
membranes will increase intracellular ROS to superior levels to those induced by endogenous ROS
(Imlay, 2008; Storz and Imlay, 1999). Therefore, mechanisms against high intracellular levels of ROS
are also important for bacteria to counteract oxidative stress induced by phagocytes. This would
explain the identification of genes in our screen that do not code for envelope components, such
as moaD1. One might hypothesise that these genes are not essential for sustaining endogenous
ROS as no significant growth defects were observed in vitro without H2O2 for these mutants (Table
1). Additionally, many of the genes identified in our screening seem to have a role in the
107 Concluding Remarks
intracellular lifestyle of M. tuberculosis, suggesting that these are important to resist against ROS
produced by host cells. However, to confirm that these proteins are specific for resistance against
phagocytic ROS, mutants’ growth in phox-deficient macrophages should be investigated.
The proteins identified in our study might thus contribute to M. tuberculosis virulence. Putative
virulence factors could be useful for designing attenuated vaccine candidates. Indeed, PPEs and
MmpL proteins have been frequently associated with virulence (Akhter et al., 2012; Domenech et
al., 2005). In a recent study, the comparative genomic analysis of free-living soil mycobacteria and
obligate parasites of the M. tuberculosis complex has shown that, along with the known gene
families related to pathogenesis such as PE/PPE genes, gene families related to biosynthesis of
Molybdenum Cofactor (MoCo) were found to be expanded in pathogenic mycobacteria. These
results suggest an important role for MoCo in the adaptation of environmental mycobacteria to
obligate pathogenesis (McGuire et al., 2012). Proteins involved in MoCo biosynthesis, such as
MoaD1, seem to represent potential virulence factors as well.
In the study of McGuire et al. (2012) it was also shown that genes related to DNA repair are
associated with adaptation of environmental mycobacteria to obligate pathogenesis. Surprisingly,
we did not select any mutant in known DNA repair genes during our screen. In E. coli, at low
concentrations (1mM) of H2O2, the main mechanism of ROS-dependent antibacterial activity is
DNA damage (Imlay and Linn, 1986). In M. tuberculosis induction of DNA repair gene expression
indicates that DNA damage occurs only at 5-10 mM H2O2 (Voskuil et al., 2011). However, bacteria
are not killed at these concentrations, suggesting that the damage does not result in DNA-
dependent killing, like in E. coli. These results suggest that M. tuberculosis DNA repair mechanisms
are highly effective in repairing the damages caused by H2O2. In addition, M. tuberculosis possesses
many genes with redundant functions, particularly in the BER pathway, one of the major
mechanisms involved in the repair of oxidative DNA damage (Dos Vultos et al., 2009; Friedberg et
al., 2006). These observations could explain why we did not identify any H2O2 sensitive mutant in
genes playing a role in DNA repair mechanisms. DNA repair mechanisms have also been suggested
to be essential for the survival of the intracellular pathogen Salmonella typhimurium (Buchmeier et
al., 1995). However, a recent study has shown that phagocytic superoxide primarily damages an
extracytoplasmic target to inhibit or kill this pathogen, suggesting that the dogma that DNA is a
primary bacterial target of the phagocytic oxidative burst needs to be re-evaluated (Craig and
Slauch, 2009).
In conclusion, our study has allowed us to identify genes involved in M. tuberculosis defence
against oxidative stress. However, there are still many genes with apparently unknown functions
that seem to have a role in such kind of mechanisms. This means that further studies are required
108 Chapter 4
to expand our knowledge about the molecular mechanisms used by M. tuberculosis to counteract
oxidative stress, particularly during macrophage infection.
Genome variability is required for bacteria to successfully adapt to constantly changing and
stressful environments, such as the ones found in human hosts or those induced by antibiotic
treatment. DNA repair, recombination and replication (3R) are important mechanisms in
generating this genomic variability (Denamur and Matic, 2006; Tonjum and Seeberg, 2001).
Therefore, analysis of polymorphisms in 3R genes can provide clues into which strains are/were
more prone to adapt and evolve. Our previous analysis of polymorphisms in 3R genes have shown
that these genes may indeed play a role in M. tuberculosis evolution and could be a useful tool for
strain discrimination (Dos Vultos et al., 2008). These results prompt us to investigate
polymorphisms in a successful group of M. tuberculosis strains, the Beijing/W family. We have
shown that different groups carrying specific polymorphisms in 3R genes exist within the Beijing/W
family (Chapter 3). It has been previously, shown that the Beijing/W family can be divided into
several groups/sublineages using other genetic markers (Hanekom et al., 2007; Tsolaki et al., 2005).
3R mechanisms might have contributed to this genetic diversity observed in Beijing/W strains.
However, an important question needs to be asked: what is the meaning of these polymorphisms?
Polymorphisms in 3R genes might have induced the accumulation of mutations conferring a
selective advantage (Denamur and Matic, 2006). Indeed, certain mutations could have conferred
some advantage to M. tuberculosis Beijing/W strains. For example, it was shown that typical
Beijing/W strains carry a high number of non-synonymous SNPs in genes coding for the regulatory
network (Schurch et al., 2011) that could result in changes in cellular processes controlled by
transcriptional regulation. These variations may play an important role in adaptation of these
bacteria to different environments and explain why typical Beijing/W strains are an emerging
phenotype (Schurch et al., 2011). A frameshift mutation in the gene encoding the DosT sensor
kinase, which senses the environmental stimuli that trigger dosR expression, was found to
correlate with the appearance of constitutive overexpression of the DosR regulon in the most
recently evolved Beijing/W sublineages (Fallow et al., 2010). Even though mutation in dosT doesn’t
seem to be directly responsible for DosR constitutive expression, its inactivation might have
induced for selection of this phenotype, which is associated with M. tuberculosis adaptation and
survival to conditions found in human lungs (Voskuil et al., 2003). Another frameshift mutation that
might have induced a selective advantage to Beijing/W strains was the one identified by us in the
mmpL9 gene given that all publicly available modern Beijing/W genomes were found to carry it.
Despite this mutation, MmpL9 seems to be functional in Beijing/W strains and to have a role in
bacterial response to oxidative stress as well as in survival inside host cells (Chapter 2). This
109 Concluding Remarks
mutation might have induced a protein change that confers a better protection to bacteria in these
conditions.
Studies in vitro (Firmani and Riley, 2002; O'Brien et al., 1994) and in animal models (Aguilar et
al., 2010; Dormans et al., 2004; Lopez et al., 2003; Palanisamy et al., 2009; Tsenova et al., 2005),
have demonstrated strain-dependent variation in key aspects of virulence such as stress survival,
transmission, pathology and lethality. On the other hand, it is also important to consider the
genetic diversity of any pathogen when identifying drug targets, vaccine antigens and developing
tools for molecular diagnostics. The analysis of 3R genes in Beijing/W strains might indicate which
strains are more prone to develop mutations conferring-drug resistance, or are more able to adapt
and persist in host cells. This is important considering that Beijing/W strains have been frequently
associated with drug resistance (Tuberculosis, 2006), and seem to have increased virulence when
compared to strains from other M. tuberculosis families (Lopez et al., 2003; Tsenova et al., 2005).
110 Chapter 4
REFERENCES
Abebe, F., and Bjune, G. (2006). The emergence of Beijing family genotypes of Mycobacterium tuberculosis and low-level protection by bacille Calmette-Guerin (BCG) vaccines: is there a link? Clinical and experimental immunology 145, 389-397. Achtman, M. (2008). Evolution, population structure, and phylogeography of genetically monomorphic bacterial pathogens. Annual review of microbiology 62, 53-70. Adams, L.B., Dinauer, M.C., Morgenstern, D.E., and Krahenbuhl, J.L. (1997). Comparison of the roles of reactive oxygen and nitrogen intermediates in the host response to Mycobacterium tuberculosis using transgenic mice. Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 78, 237-246. Aguilar, D., Hanekom, M., Mata, D., Gey van Pittius, N.C., van Helden, P.D., Warren, R.M., and Hernandez-Pando, R. (2010). Mycobacterium tuberculosis strains with the Beijing genotype demonstrate variability in virulence associated with transmission. Tuberculosis 90, 319-325. Akhter, Y., Ehebauer, M.T., Mukhopadhyay, S., and Hasnain, S.E. (2012). The PE/PPE multigene family codes for virulence factors and is a possible source of mycobacterial antigenic variation: perhaps more? Biochimie 94, 110-116. Akif, M., Khare, G., Tyagi, A.K., Mande, S.C., and Sardesai, A.A. (2008). Functional studies of multiple thioredoxins from Mycobacterium tuberculosis. Journal of bacteriology 190, 7087-7095. Akira, S., Uematsu, S., and Takeuchi, O. (2006). Pathogen recognition and innate immunity. Cell 124, 783-801. Alam, M.S., Garg, S.K., and Agrawal, P. (2009). Studies on structural and functional divergence among seven WhiB proteins of Mycobacterium tuberculosis H37Rv. The FEBS journal 276, 76-93. Alland, D., Lacher, D.W., Hazbon, M.H., Motiwala, A.S., Qi, W., Fleischmann, R.D., and Whittam, T.S. (2007). Role of large sequence polymorphisms (LSPs) in generating genomic diversity among clinical isolates of Mycobacterium tuberculosis and the utility of LSPs in phylogenetic analysis. Journal of clinical microbiology 45, 39-46. Andersson, D.I., and Levin, B.R. (1999). The biological cost of antibiotic resistance. Current opinion in microbiology 2, 489-493. Armstrong, J.A., and Hart, P.D. (1971). Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes. The Journal of experimental medicine 134, 713-740. Armstrong, J.A., and Hart, P.D. (1975). Phagosome-lysosome interactions in cultured macrophages infected with virulent tubercle bacilli. Reversal of the usual nonfusion pattern and observations on bacterial survival. The Journal of experimental medicine 142, 1-16. Astarie-Dequeker, C., N'Diaye, E.N., Le Cabec, V., Rittig, M.G., Prandi, J., and Maridonneau-Parini, I. (1999). The mannose receptor mediates uptake of pathogenic and nonpathogenic mycobacteria and bypasses bactericidal responses in human macrophages. Infection and immunity 67, 469-477. Aston, C., Rom, W.N., Talbot, A.T., and Reibman, J. (1998). Early inhibition of mycobacterial growth by human alveolar macrophages is not due to nitric oxide. American journal of respiratory and critical care medicine 157, 1943-1950. Bach, H., Papavinasasundaram, K.G., Wong, D., Hmama, Z., and Av-Gay, Y. (2008). Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation of human vacuolar protein sorting 33B. Cell host & microbe 3, 316-322. Baker, L., Brown, T., Maiden, M.C., and Drobniewski, F. (2004). Silent nucleotide polymorphisms and a phylogeny for Mycobacterium tuberculosis. Emerging infectious diseases 10, 1568-1577. Bandelt, H.J., Forster, P., and Rohl, A. (1999). Median-joining networks for inferring intraspecific phylogenies. Molecular biology and evolution 16, 37-48.
112 References
Bange, F.C., Collins, F.M., and Jacobs, W.R., Jr. (1999). Survival of mice infected with Mycobacterium smegmatis containing large DNA fragments from Mycobacterium tuberculosis. Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 79, 171-180. Baranov, P.V., Gurvich, O.L., Fayet, O., Prere, M.F., Miller, W.A., Gesteland, R.F., Atkins, J.F., and Giddings, M.C. (2001). RECODE: a database of frameshifting, bypassing and codon redefinition utilized for gene expression. Nucleic Acids Res 29, 264-267. Barreiro, L.B., Neyrolles, O., Babb, C.L., Tailleux, L., Quach, H., McElreavey, K., Helden, P.D., Hoal, E.G., Gicquel, B., and Quintana-Murci, L. (2006). Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis. PLoS medicine 3, e20. Bedard, K., and Krause, K.H. (2007). The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiological reviews 87, 245-313. Bergval, I.L., Klatser, P.R., Schuitema, A.R., Oskam, L., and Anthony, R.M. (2007). Specific mutations in the Mycobacterium tuberculosis rpoB gene are associated with increased dnaE2 expression. FEMS microbiology letters 275, 338-343. Bifani, P.J., Mathema, B., Kurepina, N.E., and Kreiswirth, B.N. (2002). Global dissemination of the Mycobacterium tuberculosis W-Beijing family strains. Trends in microbiology 10, 45-52. Bifani, P.J., Plikaytis, B.B., Kapur, V., Stockbauer, K., Pan, X., Lutfey, M.L., Moghazeh, S.L., Eisner, W., Daniel, T.M., Kaplan, M.H., et al. (1996). Origin and interstate spread of a New York City multidrug-resistant Mycobacterium tuberculosis clone family. JAMA : the journal of the American Medical Association 275, 452-457. Biswas, T., Small, J., Vandal, O., Odaira, T., Deng, H., Ehrt, S., and Tsodikov, O.V. (2010). Structural insight into serine protease Rv3671c that Protects M. tuberculosis from oxidative and acidic stress. Structure 18, 1353-1363. Bjelland, S., Bjoras, M., and Seeberg, E. (1993). Excision of 3-methylguanine from alkylated DNA by 3-methyladenine DNA glycosylase I of Escherichia coli. Nucleic Acids Res 21, 2045-2049. Boshoff, H.I., Myers, T.G., Copp, B.R., McNeil, M.R., Wilson, M.A., and Barry, C.E., 3rd (2004). The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. The Journal of biological chemistry 279, 40174-40184. Boshoff, H.I., Reed, M.B., Barry, C.E., 3rd, and Mizrahi, V. (2003). DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis. Cell 113, 183-193. Brennan, P.J., and Nikaido, H. (1995). The envelope of mycobacteria. Annual review of biochemistry 64, 29-63. Brodin, P., Poquet, Y., Levillain, F., Peguillet, I., Larrouy-Maumus, G., Gilleron, M., Ewann, F., Christophe, T., Fenistein, D., Jang, J., et al. (2010). High content phenotypic cell-based visual screen identifies Mycobacterium tuberculosis acyltrehalose-containing glycolipids involved in phagosome remodeling. PLoS pathogens 6, e1001100. Brooks, P.C., Movahedzadeh, F., and Davis, E.O. (2001). Identification of some DNA damage-inducible genes of Mycobacterium tuberculosis: apparent lack of correlation with LexA binding. Journal of bacteriology 183, 4459-4467. Brosch, R., Gordon, S.V., Marmiesse, M., Brodin, P., Buchrieser, C., Eiglmeier, K., Garnier, T., Gutierrez, C., Hewinson, G., Kremer, K., et al. (2002). A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proceedings of the National Academy of Sciences of the United States of America 99, 3684-3689. Brudey, K., Driscoll, J.R., Rigouts, L., Prodinger, W.M., Gori, A., Al-Hajoj, S.A., Allix, C., Aristimuno, L., Arora, J., Baumanis, V., et al. (2006). Mycobacterium tuberculosis complex genetic diversity: mining the fourth international spoligotyping database (SpolDB4) for classification, population genetics and epidemiology. BMC microbiology 6, 23. Bryk, R., Lima, C.D., Erdjument-Bromage, H., Tempst, P., and Nathan, C. (2002). Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science 295, 1073-1077.
113 References
Buchmeier, N.A., Libby, S.J., Xu, Y., Loewen, P.C., Switala, J., Guiney, D.G., and Fang, F.C. (1995). DNA repair is more important than catalase for Salmonella virulence in mice. The Journal of clinical investigation 95, 1047-1053. Buchmeier, N.A., Newton, G.L., and Fahey, R.C. (2006). A mycothiol synthase mutant of Mycobacterium tuberculosis has an altered thiol-disulfide content and limited tolerance to stress. Journal of bacteriology 188, 6245-6252. Buchmeier, N.A., Newton, G.L., Koledin, T., and Fahey, R.C. (2003). Association of mycothiol with protection of Mycobacterium tuberculosis from toxic oxidants and antibiotics. Molecular microbiology 47, 1723-1732. Bustamante, J., Aksu, G., Vogt, G., de Beaucoudrey, L., Genel, F., Chapgier, A., Filipe-Santos, O., Feinberg, J., Emile, J.F., Kutukculer, N., et al. (2007). BCG-osis and tuberculosis in a child with chronic granulomatous disease. The Journal of allergy and clinical immunology 120, 32-38. Bylund, J., Brown, K.L., Movitz, C., Dahlgren, C., and Karlsson, A. (2010). Intracellular generation of superoxide by the phagocyte NADPH oxidase: how, where, and what for? Free radical biology & medicine 49, 1834-1845. Cabusora, L., Sutton, E., Fulmer, A., and Forst, C.V. (2005). Differential network expression during drug and stress response. Bioinformatics 21, 2898-2905. Calmette, A. (1931). Preventive Vaccination Against Tuberculosis with BCG. Proceedings of the Royal Society of Medicine 24, 1481-1490. Camacho, L.R., Constant, P., Raynaud, C., Laneelle, M.A., Triccas, J.A., Gicquel, B., Daffe, M., and Guilhot, C. (2001). Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis. Evidence that this lipid is involved in the cell wall permeability barrier. The Journal of biological chemistry 276, 19845-19854. Camacho, L.R., Ensergueix, D., Perez, E., Gicquel, B., and Guilhot, C. (1999). Identification of a virulence gene cluster of Mycobacterium tuberculosis by signature-tagged transposon mutagenesis. Molecular microbiology 34, 257-267. Caminero, J.A., Pena, M.J., Campos-Herrero, M.I., Rodriguez, J.C., Garcia, I., Cabrera, P., Lafoz, C., Samper, S., Takiff, H., Afonso, O., et al. (2001). Epidemiological evidence of the spread of a Mycobacterium tuberculosis strain of the Beijing genotype on Gran Canaria Island. American journal of respiratory and critical care medicine 164, 1165-1170. Cappelli, G., Volpe, E., Grassi, M., Liseo, B., Colizzi, V., and Mariani, F. (2006). Profiling of Mycobacterium tuberculosis gene expression during human macrophage infection: upregulation of the alternative sigma factor G, a group of transcriptional regulators, and proteins with unknown function. Research in microbiology 157, 445-455. Catalao, M.J., Gil, F., Moniz-Pereira, J., Sao-Jose, C., and Pimentel, M. (2012). Diversity in bacterial lysis systems: bacteriophages show the way. FEMS microbiology reviews. Caws, M., Thwaites, G., Dunstan, S., Hawn, T.R., Lan, N.T., Thuong, N.T., Stepniewska, K., Huyen, M.N., Bang, N.D., Loc, T.H., et al. (2008). The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PLoS pathogens 4, e1000034. Chan, J., Fan, X.D., Hunter, S.W., Brennan, P.J., and Bloom, B.R. (1991). Lipoarabinomannan, a possible virulence factor involved in persistence of Mycobacterium tuberculosis within macrophages. Infection and immunity 59, 1755-1761. Chan, J., Fujiwara, T., Brennan, P., McNeil, M., Turco, S.J., Sibille, J.C., Snapper, M., Aisen, P., and Bloom, B.R. (1989). Microbial glycolipids: possible virulence factors that scavenge oxygen radicals. Proceedings of the National Academy of Sciences of the United States of America 86, 2453-2457. Chan, J., Xing, Y., Magliozzo, R.S., and Bloom, B.R. (1992). Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages. The Journal of experimental medicine 175, 1111-1122. Chao, J., Wong, D., Zheng, X., Poirier, V., Bach, H., Hmama, Z., and Av-Gay, Y. (2010). Protein kinase and phosphatase signaling in Mycobacterium tuberculosis physiology and pathogenesis. Biochimica et biophysica acta 1804, 620-627.
114 References
Chaturvedi, R., Bansal, K., Narayana, Y., Kapoor, N., Sukumar, N., Togarsimalemath, S.K., Chandra, N., Mishra, S., Ajitkumar, P., Joshi, B., et al. (2010). The multifunctional PE_PGRS11 protein from Mycobacterium tuberculosis plays a role in regulating resistance to oxidative stress. The Journal of biological chemistry 285, 30389-30403. Chen, J., Tsolaki, A.G., Shen, X., Jiang, X., Mei, J., and Gao, Q. (2007). Deletion-targeted multiplex PCR (DTM-PCR) for identification of Beijing/W genotypes of Mycobacterium tuberculosis. Tuberculosis 87, 446-449. Cheng, K.C., Cahill, D.S., Kasai, H., Nishimura, S., and Loeb, L.A. (1992). 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G----T and A----C substitutions. The Journal of biological chemistry 267, 166-172. Choi, H.S., Rai, P.R., Chu, H.W., Cool, C., and Chan, E.D. (2002). Analysis of nitric oxide synthase and nitrotyrosine expression in human pulmonary tuberculosis. American journal of respiratory and critical care medicine 166, 178-186. Cirillo, S.L., Subbian, S., Chen, B., Weisbrod, T.R., Jacobs, W.R., Jr., and Cirillo, J.D. (2009). Protection of Mycobacterium tuberculosis from reactive oxygen species conferred by the mel2 locus impacts persistence and dissemination. Infection and immunity 77, 2557-2567. Clay, H., Davis, J.M., Beery, D., Huttenlocher, A., Lyons, S.E., and Ramakrishnan, L. (2007). Dichotomous role of the macrophage in early Mycobacterium marinum infection of the zebrafish. Cell host & microbe 2, 29-39. Clemens, D.L., and Horwitz, M.A. (1996). The Mycobacterium tuberculosis phagosome interacts with early endosomes and is accessible to exogenously administered transferrin. The Journal of experimental medicine 184, 1349-1355. Colangeli, R., Haq, A., Arcus, V.L., Summers, E., Magliozzo, R.S., McBride, A., Mitra, A.K., Radjainia, M., Khajo, A., Jacobs, W.R., Jr., et al. (2009). The multifunctional histone-like protein Lsr2 protects mycobacteria against reactive oxygen intermediates. Proceedings of the National Academy of Sciences of the United States of America 106, 4414-4418. Colditz, G.A., Brewer, T.F., Berkey, C.S., Wilson, M.E., Burdick, E., Fineberg, H.V., and Mosteller, F. (1994). Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA : the journal of the American Medical Association 271, 698-702. Cole, S.T., Brosch, R., Parkhill, J., Garnier, T., Churcher, C., Harris, D., Gordon, S.V., Eiglmeier, K., Gas, S., Barry, C.E., 3rd, et al. (1998). Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537-544. Comas, I., Chakravartti, J., Small, P.M., Galagan, J., Niemann, S., Kremer, K., Ernst, J.D., and Gagneux, S. (2010). Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved. Nature genetics 42, 498-503. Comas, I., and Gagneux, S. (2009). The past and future of tuberculosis research. PLoS pathogens 5, e1000600. Comas, I., Homolka, S., Niemann, S., and Gagneux, S. (2009). Genotyping of genetically monomorphic bacteria: DNA sequencing in Mycobacterium tuberculosis highlights the limitations of current methodologies. PloS one 4, e7815. Converse, S.E., Mougous, J.D., Leavell, M.D., Leary, J.A., Bertozzi, C.R., and Cox, J.S. (2003). MmpL8 is required for sulfolipid-1 biosynthesis and Mycobacterium tuberculosis virulence. Proceedings of the National Academy of Sciences of the United States of America 100, 6121-6126. Cooper, A.M., Pearl, J.E., Brooks, J.V., Ehlers, S., and Orme, I.M. (2000). Expression of the nitric oxide synthase 2 gene is not essential for early control of Mycobacterium tuberculosis in the murine lung. Infection and immunity 68, 6879-6882. Coscolla, M., and Gagneux, S. (2010). Does M. tuberculosis genomic diversity explain disease diversity? Drug discovery today Disease mechanisms 7, e43-e59. Cox, J.S., Chen, B., McNeil, M., and Jacobs, W.R., Jr. (1999). Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice. Nature 402, 79-83. Craig, M., and Slauch, J.M. (2009). Phagocytic superoxide specifically damages an extracytoplasmic target to inhibit or kill Salmonella. PloS one 4, e4975.
115 References
Daffe, M., and Draper, P. (1998). The envelope layers of mycobacteria with reference to their pathogenicity. Advances in microbial physiology 39, 131-203. Daniel, T.M. (2006). The history of tuberculosis. Respiratory medicine 100, 1862-1870. Darwin, K.H., Ehrt, S., Gutierrez-Ramos, J.C., Weich, N., and Nathan, C.F. (2003). The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science 302, 1963-1966. Darwin, K.H., and Nathan, C.F. (2005). Role for nucleotide excision repair in virulence of Mycobacterium tuberculosis. Infection and immunity 73, 4581-4587. David, S.S., O'Shea, V.L., and Kundu, S. (2007). Base-excision repair of oxidative DNA damage. Nature 447, 941-950. Day, J.H., Grant, A.D., Fielding, K.L., Morris, L., Moloi, V., Charalambous, S., Puren, A.J., Chaisson, R.E., De Cock, K.M., Hayes, R.J., et al. (2004). Does tuberculosis increase HIV load? The Journal of infectious diseases 190, 1677-1684. de Hostos, E.L. (1999). The coronin family of actin-associated proteins. Trends in cell biology 9, 345-350. de Jong, B.C., Hill, P.C., Brookes, R.H., Gagneux, S., Jeffries, D.J., Otu, J.K., Donkor, S.A., Fox, A., McAdam, K.P., Small, P.M., et al. (2006). Mycobacterium africanum elicits an attenuated T cell response to early secreted antigenic target, 6 kDa, in patients with tuberculosis and their household contacts. The Journal of infectious diseases 193, 1279-1286. de Laat, W.L., Jaspers, N.G., and Hoeijmakers, J.H. (1999). Molecular mechanism of nucleotide excision repair. Genes Dev 13, 768-785. Deghmane, A.E., Soualhine, H., Bach, H., Sendide, K., Itoh, S., Tam, A., Noubir, S., Talal, A., Lo, R., Toyoshima, S., et al. (2007). Lipoamide dehydrogenase mediates retention of coronin-1 on BCG vacuoles, leading to arrest in phagosome maturation. Journal of cell science 120, 2796-2806. Della, M., Palmbos, P.L., Tseng, H.M., Tonkin, L.M., Daley, J.M., Topper, L.M., Pitcher, R.S., Tomkinson, A.E., Wilson, T.E., and Doherty, A.J. (2004). Mycobacterial Ku and ligase proteins constitute a two-component NHEJ repair machine. Science 306, 683-685. Demple, B., and Harrison, L. (1994). Repair of oxidative damage to DNA: enzymology and biology. Annual review of biochemistry 63, 915-948. Denamur, E., and Matic, I. (2006). Evolution of mutation rates in bacteria. Molecular microbiology 60, 820-827. Denu, J.M., and Tanner, K.G. (1998). Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation. Biochemistry 37, 5633-5642. Deretic, V., Philipp, W., Dhandayuthapani, S., Mudd, M.H., Curcic, R., Garbe, T., Heym, B., Via, L.E., and Cole, S.T. (1995). Mycobacterium tuberculosis is a natural mutant with an inactivated oxidative-stress regulatory gene: implications for sensitivity to isoniazid. Molecular microbiology 17, 889-900. Desjardins, M., Huber, L.A., Parton, R.G., and Griffiths, G. (1994). Biogenesis of phagolysosomes proceeds through a sequential series of interactions with the endocytic apparatus. The Journal of cell biology 124, 677-688. Dianov, G., and Lindahl, T. (1994). Reconstitution of the DNA base excision-repair pathway. Curr Biol 4, 1069-1076. Dizdaroglu, M. (2005). Base-excision repair of oxidative DNA damage by DNA glycosylases. Mutation research 591, 45-59. Domenech, P., Honore, N., Heym, B., and Cole, S.T. (2001). Role of OxyS of Mycobacterium tuberculosis in oxidative stress: overexpression confers increased sensitivity to organic hydroperoxides. Microbes and infection / Institut Pasteur 3, 713-721. Domenech, P., Reed, M.B., and Barry, C.E., 3rd (2005). Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infection and immunity 73, 3492-3501. Domenech, P., Reed, M.B., Dowd, C.S., Manca, C., Kaplan, G., and Barry, C.E., 3rd (2004). The role of MmpL8 in sulfatide biogenesis and virulence of Mycobacterium tuberculosis. The Journal of biological chemistry 279, 21257-21265. Dormans, J., Burger, M., Aguilar, D., Hernandez-Pando, R., Kremer, K., Roholl, P., Arend, S.M., and van Soolingen, D. (2004). Correlation of virulence, lung pathology, bacterial load and delayed type
116 References
hypersensitivity responses after infection with different Mycobacterium tuberculosis genotypes in a BALB/c mouse model. Clinical and experimental immunology 137, 460-468. Dos Vultos, T., Blazquez, J., Rauzier, J., Matic, I., and Gicquel, B. (2006). Identification of Nudix hydrolase family members with an antimutator role in Mycobacterium tuberculosis and Mycobacterium smegmatis. Journal of bacteriology 188, 3159-3161. Dos Vultos, T., Mestre, O., Rauzier, J., Golec, M., Rastogi, N., Rasolofo, V., Tonjum, T., Sola, C., Matic, I., and Gicquel, B. (2008). Evolution and diversity of clonal bacteria: the paradigm of Mycobacterium tuberculosis. PloS one 3, e1538. Dos Vultos, T., Mestre, O., Tonjum, T., and Gicquel, B. (2009). DNA repair in Mycobacterium tuberculosis revisited. FEMS microbiology reviews 33, 471-487. Drennan, M.B., Nicolle, D., Quesniaux, V.J., Jacobs, M., Allie, N., Mpagi, J., Fremond, C., Wagner, H., Kirschning, C., and Ryffel, B. (2004). Toll-like receptor 2-deficient mice succumb to Mycobacterium tuberculosis infection. The American journal of pathology 164, 49-57. Durbach, S.I., Springer, B., Machowski, E.E., North, R.J., Papavinasasundaram, K.G., Colston, M.J., Bottger, E.C., and Mizrahi, V. (2003). DNA alkylation damage as a sensor of nitrosative stress in Mycobacterium tuberculosis. Infection and immunity 71, 997-1000. Dussurget, O., Stewart, G., Neyrolles, O., Pescher, P., Young, D., and Marchal, G. (2001). Role of Mycobacterium tuberculosis copper-zinc superoxide dismutase. Infection and immunity 69, 529-533. Dutta, N.K., Mehra, S., Didier, P.J., Roy, C.J., Doyle, L.A., Alvarez, X., Ratterree, M., Be, N.A., Lamichhane, G., Jain, S.K., et al. (2010). Genetic requirements for the survival of tubercle bacilli in primates. The Journal of infectious diseases 201, 1743-1752. Dworkin, M., Falkow, S., Rosenberg, E., Schleifer, K.-H., and Stackebrandt, E. (2006). The Prokaryotes: Proteobacteria:gamma subclass, Vol 3 (Springer). Ebrahimi-Rad, M., Bifani, P., Martin, C., Kremer, K., Samper, S., Rauzier, J., Kreiswirth, B., Blazquez, J., Jouan, M., van Soolingen, D., et al. (2003). Mutations in putative mutator genes of Mycobacterium tuberculosis strains of the W-Beijing family. Emerging infectious diseases 9, 838-845. Edwards, K.M., Cynamon, M.H., Voladri, R.K., Hager, C.C., DeStefano, M.S., Tham, K.T., Lakey, D.L., Bochan, M.R., and Kernodle, D.S. (2001). Iron-cofactored superoxide dismutase inhibits host responses to Mycobacterium tuberculosis. American journal of respiratory and critical care medicine 164, 2213-2219. Ehrt, S., and Schnappinger, D. (2009). Mycobacterial survival strategies in the phagosome: defence against host stresses. Cellular microbiology 11, 1170-1178. Embley, T.M., and Stackebrandt, E. (1994). The molecular phylogeny and systematics of the actinomycetes. Annual review of microbiology 48, 257-289. Ezraty, B., Bos, J., Barras, F., and Aussel, L. (2005). Methionine sulfoxide reduction and assimilation in Escherichia coli: new role for the biotin sulfoxide reductase BisC. Journal of bacteriology 187, 231-237. Facchetti, F., Vermi, W., Fiorentini, S., Chilosi, M., Caruso, A., Duse, M., Notarangelo, L.D., and Badolato, R. (1999). Expression of inducible nitric oxide synthase in human granulomas and histiocytic reactions. The American journal of pathology 154, 145-152. Fallow, A., Domenech, P., and Reed, M.B. (2010). Strains of the East Asian (W/Beijing) lineage of Mycobacterium tuberculosis are DosS/DosT-DosR two-component regulatory system natural mutants. Journal of bacteriology 192, 2228-2238. Fang, F.C. (2004). Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nature reviews Microbiology 2, 820-832. Fenner, L., Egger, M., Bodmer, T., Altpeter, E., Zwahlen, M., Jaton, K., Pfyffer, G.E., Borrell, S., Dubuis, O., Bruderer, T., et al. (2012). Effect of mutation and genetic background on drug resistance in Mycobacterium tuberculosis. Antimicrobial agents and chemotherapy 56, 3047-3053. Ferrer, N.L., Gomez, A.B., Neyrolles, O., Gicquel, B., and Martin, C. (2010). Interactions of attenuated Mycobacterium tuberculosis phoP mutant with human macrophages. PloS one 5, e12978. Ferwerda, G., Girardin, S.E., Kullberg, B.J., Le Bourhis, L., de Jong, D.J., Langenberg, D.M., van Crevel, R., Adema, G.J., Ottenhoff, T.H., Van der Meer, J.W., et al. (2005). NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS pathogens 1, 279-285.
117 References
Filliol, I., Driscoll, J.R., Van Soolingen, D., Kreiswirth, B.N., Kremer, K., Valetudie, G., Anh, D.D., Barlow, R., Banerjee, D., Bifani, P.J., et al. (2002). Global distribution of Mycobacterium tuberculosis spoligotypes. Emerging infectious diseases 8, 1347-1349. Filliol, I., Motiwala, A.S., Cavatore, M., Qi, W., Hazbon, M.H., Bobadilla del Valle, M., Fyfe, J., Garcia-Garcia, L., Rastogi, N., Sola, C., et al. (2006). Global phylogeny of Mycobacterium tuberculosis based on single nucleotide polymorphism (SNP) analysis: insights into tuberculosis evolution, phylogenetic accuracy of other DNA fingerprinting systems, and recommendations for a minimal standard SNP set. Journal of bacteriology 188, 759-772. Fine, P.E. (1995). Variation in protection by BCG: implications of and for heterologous immunity. Lancet 346, 1339-1345. Firmani, M.A., and Riley, L.W. (2002). Mycobacterium tuberculosis CDC1551 is resistant to reactive nitrogen and oxygen intermediates in vitro. Infection and immunity 70, 3965-3968. Flannagan, R.S., Cosio, G., and Grinstein, S. (2009). Antimicrobial mechanisms of phagocytes and bacterial evasion strategies. Nature reviews Microbiology 7, 355-366. Fleischmann, R.D., Alland, D., Eisen, J.A., Carpenter, L., White, O., Peterson, J., DeBoy, R., Dodson, R., Gwinn, M., Haft, D., et al. (2002). Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. Journal of bacteriology 184, 5479-5490. Flynn, J.L., Chan, J., and Lin, P.L. (2011). Macrophages and control of granulomatous inflammation in tuberculosis. Mucosal immunology 4, 271-278. Fontan, P., Aris, V., Ghanny, S., Soteropoulos, P., and Smith, I. (2008). Global transcriptional profile of Mycobacterium tuberculosis during THP-1 human macrophage infection. Infection and immunity 76, 717-725. Friedberg, E.C., Walker, G.C., Siede, W., Wood, R.D., Schultz, R.A., and Ellenberger, T. (2006). DNA repair and mutagenesis, 2nd ed. edn (ASM press, Washington, DC.). Frothingham, R., and Meeker-O'Connell, W.A. (1998). Genetic diversity in the Mycobacterium tuberculosis complex based on variable numbers of tandem DNA repeats. Microbiology 144 ( Pt 5), 1189-1196. Fu, L.M., and Shinnick, T.M. (2007). Genome-wide exploration of the drug action of capreomycin on Mycobacterium tuberculosis using Affymetrix oligonucleotide GeneChips. The Journal of infection 54, 277-284. Gagneux, S., DeRiemer, K., Van, T., Kato-Maeda, M., de Jong, B.C., Narayanan, S., Nicol, M., Niemann, S., Kremer, K., Gutierrez, M.C., et al. (2006a). Variable host-pathogen compatibility in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America 103, 2869-2873. Gagneux, S., Long, C.D., Small, P.M., Van, T., Schoolnik, G.K., and Bohannan, B.J. (2006b). The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 312, 1944-1946. Gamulin, V., Cetkovic, H., and Ahel, I. (2004). Identification of a promoter motif regulating the major DNA damage response mechanism of Mycobacterium tuberculosis. FEMS microbiology letters 238, 57-63. Gandhi, N.R., Nunn, P., Dheda, K., Schaaf, H.S., Zignol, M., van Soolingen, D., Jensen, P., and Bayona, J. (2010). Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis. Lancet 375, 1830-1843. Garbe, T.R., Hibler, N.S., and Deretic, V. (1996). Response of Mycobacterium tuberculosis to reactive oxygen and nitrogen intermediates. Mol Med 2, 134-142. Gebhard, S., Humpel, A., McLellan, A.D., and Cook, G.M. (2008). The alternative sigma factor SigF of Mycobacterium smegmatis is required for survival of heat shock, acidic pH and oxidative stress. Microbiology 154, 2786-2795. Geijtenbeek, T.B., Van Vliet, S.J., Koppel, E.A., Sanchez-Hernandez, M., Vandenbroucke-Grauls, C.M., Appelmelk, B., and Van Kooyk, Y. (2003). Mycobacteria target DC-SIGN to suppress dendritic cell function. The Journal of experimental medicine 197, 7-17.
118 References
Geiman, D.E., Raghunand, T.R., Agarwal, N., and Bishai, W.R. (2006). Differential gene expression in response to exposure to antimycobacterial agents and other stress conditions among seven Mycobacterium tuberculosis whiB-like genes. Antimicrobial agents and chemotherapy 50, 2836-2841. Glynn, J.R., Whiteley, J., Bifani, P.J., Kremer, K., and van Soolingen, D. (2002). Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Emerging infectious diseases 8, 843-849. Gong, C., Bongiorno, P., Martins, A., Stephanou, N.C., Zhu, H., Shuman, S., and Glickman, M.S. (2005). Mechanism of nonhomologous end-joining in mycobacteria: a low-fidelity repair system driven by Ku, ligase D and ligase C. Nat Struct Mol Biol 12, 304-312. Gonzalo-Asensio, J., Mostowy, S., Harders-Westerveen, J., Huygen, K., Hernandez-Pando, R., Thole, J., Behr, M., Gicquel, B., and Martin, C. (2008). PhoP: a missing piece in the intricate puzzle of Mycobacterium tuberculosis virulence. PloS one 3, e3496. Graham, J.E., and Clark-Curtiss, J.E. (1999). Identification of Mycobacterium tuberculosis RNAs synthesized in response to phagocytosis by human macrophages by selective capture of transcribed sequences (SCOTS). Proceedings of the National Academy of Sciences of the United States of America 96, 11554-11559. Grant, S.S., Kaufmann, B.B., Chand, N.S., Haseley, N., and Hung, D.T. (2012). Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals. Proceedings of the National Academy of Sciences of the United States of America 109, 12147-12152. Griffiths, G., Nystrom, B., Sable, S.B., and Khuller, G.K. (2010). Nanobead-based interventions for the treatment and prevention of tuberculosis. Nature reviews Microbiology 8, 827-834. Grzegorzewicz, A.E., Pham, H., Gundi, V.A., Scherman, M.S., North, E.J., Hess, T., Jones, V., Gruppo, V., Born, S.E., Kordulakova, J., et al. (2012). Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nature chemical biology 8, 334-341. Guo, Y., Bandaru, V., Jaruga, P., Zhao, X., Burrows, C.J., Iwai, S., Dizdaroglu, M., Bond, J.P., and Wallace, S.S. (2010). The oxidative DNA glycosylases of Mycobacterium tuberculosis exhibit different substrate preferences from their Escherichia coli counterparts. DNA repair 9, 177-190. Gurtler, V., Mayall, B.C., and Seviour, R. (2004). Can whole genome analysis refine the taxonomy of the genus Rhodococcus? FEMS microbiology reviews 28, 377-403. Gutacker, M.M., Mathema, B., Soini, H., Shashkina, E., Kreiswirth, B.N., Graviss, E.A., and Musser, J.M. (2006). Single-nucleotide polymorphism-based population genetic analysis of Mycobacterium tuberculosis strains from 4 geographic sites. The Journal of infectious diseases 193, 121-128. Gutacker, M.M., Smoot, J.C., Migliaccio, C.A., Ricklefs, S.M., Hua, S., Cousins, D.V., Graviss, E.A., Shashkina, E., Kreiswirth, B.N., and Musser, J.M. (2002). Genome-wide analysis of synonymous single nucleotide polymorphisms in Mycobacterium tuberculosis complex organisms: resolution of genetic relationships among closely related microbial strains. Genetics 162, 1533-1543. Guthlein, C., Wanner, R.M., Sander, P., Davis, E.O., Bosshard, M., Jiricny, J., Bottger, E.C., and Springer, B. (2008). Characterisation of the mycobacterial NER system reveals novel functions of uvrD1 helicase. Journal of bacteriology. Gutierrez, M.C., Brisse, S., Brosch, R., Fabre, M., Omais, B., Marmiesse, M., Supply, P., and Vincent, V. (2005). Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis. PLoS pathogens 1, e5. Hanekom, M., van der Spuy, G.D., Streicher, E., Ndabambi, S.L., McEvoy, C.R., Kidd, M., Beyers, N., Victor, T.C., van Helden, P.D., and Warren, R.M. (2007). A recently evolved sublineage of the Mycobacterium tuberculosis Beijing strain family is associated with an increased ability to spread and cause disease. Journal of clinical microbiology 45, 1483-1490. Harries, A.D., and Dye, C. (2006). Tuberculosis. Ann Trop Med Parasitol 100, 415-431. Hershberg, R., Lipatov, M., Small, P.M., Sheffer, H., Niemann, S., Homolka, S., Roach, J.C., Kremer, K., Petrov, D.A., Feldman, M.W., et al. (2008). High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography. PLoS Biol 6, e311.
119 References
Heym, B., Honore, N., Truffot-Pernot, C., Banerjee, A., Schurra, C., Jacobs, W.R., Jr., van Embden, J.D., Grosset, J.H., and Cole, S.T. (1994). Implications of multidrug resistance for the future of short-course chemotherapy of tuberculosis: a molecular study. Lancet 344, 293-298. Heym, B., Zhang, Y., Poulet, S., Young, D., and Cole, S.T. (1993). Characterization of the katG gene encoding a catalase-peroxidase required for the isoniazid susceptibility of Mycobacterium tuberculosis. Journal of bacteriology 175, 4255-4259. Heyworth, P.G., Cross, A.R., and Curnutte, J.T. (2003). Chronic granulomatous disease. Current opinion in immunology 15, 578-584. Hiriyanna, K.T., and Ramakrishnan, T. (1986). Deoxyribonucleic acid replication time in Mycobacterium tuberculosis H37 Rv. Archives of microbiology 144, 105-109. Hoffmann, C., Leis, A., Niederweis, M., Plitzko, J.M., and Engelhardt, H. (2008). Disclosure of the mycobacterial outer membrane: cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proceedings of the National Academy of Sciences of the United States of America 105, 3963-3967. Holmgren, A. (2000). Antioxidant function of thioredoxin and glutaredoxin systems. Antioxidants & redox signaling 2, 811-820. Homolka, S., Niemann, S., Russell, D.G., and Rohde, K.H. (2010). Functional genetic diversity among Mycobacterium tuberculosis complex clinical isolates: delineation of conserved core and lineage-specific transcriptomes during intracellular survival. PLoS pathogens 6, e1000988. Houghton, J., Townsend, C., Williams, A.R., Rodgers, A., Rand, L., Walker, K.B., Bottger, E.C., Springer, B., and Davis, E.O. (2012). Important role for Mycobacterium tuberculosis UvrD1 in pathogenesis and persistence apart from its function in nucleotide excision repair. Journal of bacteriology 194, 2916-2923. Hu, Y., Kendall, S., Stoker, N.G., and Coates, A.R. (2004). The Mycobacterium tuberculosis sigJ gene controls sensitivity of the bacterium to hydrogen peroxide. FEMS microbiology letters 237, 415-423. Humphreys, I.R., Stewart, G.R., Turner, D.J., Patel, J., Karamanou, D., Snelgrove, R.J., and Young, D.B. (2006). A role for dendritic cells in the dissemination of mycobacterial infection. Microbes and infection / Institut Pasteur 8, 1339-1346. Imlay, J.A. (2008). Cellular defenses against superoxide and hydrogen peroxide. Annual review of biochemistry 77, 755-776. Imlay, J.A., and Linn, S. (1986). Bimodal pattern of killing of DNA-repair-defective or anoxically grown Escherichia coli by hydrogen peroxide. Journal of bacteriology 166, 519-527. Ishibashi, Y., and Arai, T. (1990). Roles of the complement receptor type 1 (CR1) and type 3 (CR3) on phagocytosis and subsequent phagosome-lysosome fusion in Salmonella-infected murine macrophages. FEMS microbiology immunology 2, 89-96. Iwamoto, T., Yoshida, S., Suzuki, K., Tomita, M., Fujiyama, R., Tanaka, N., Kawakami, Y., and Ito, M. (2007). Hypervariable loci that enhance the discriminatory ability of newly proposed 15-loci and 24-loci variable-number tandem repeat typing method on Mycobacterium tuberculosis strains predominated by the Beijing family. FEMS microbiology letters 270, 67-74. Iwamoto, T., Yoshida, S., Suzuki, K., and Wada, T. (2008). Population structure analysis of the Mycobacterium tuberculosis Beijing family indicates an association between certain sublineages and multidrug resistance. Antimicrobial agents and chemotherapy 52, 3805-3809. Jain, M., and Cox, J.S. (2005). Interaction between polyketide synthase and transporter suggests coupled synthesis and export of virulence lipid in M. tuberculosis. PLoS pathogens 1, e2. Jain, R., Dey, B., Khera, A., Srivastav, P., Gupta, U.D., Katoch, V.M., Ramanathan, V.D., and Tyagi, A.K. (2011). Over-expression of superoxide dismutase obliterates the protective effect of BCG against tuberculosis by modulating innate and adaptive immune responses. Vaccine 29, 8118-8125. Jain, R., Kumar, P., and Varshney, U. (2007). A distinct role of formamidopyrimidine DNA glycosylase (MutM) in down-regulation of accumulation of G, C mutations and protection against oxidative stress in mycobacteria. DNA repair 6, 1774-1785. Jarlier, V., and Nikaido, H. (1994). Mycobacterial cell wall: structure and role in natural resistance to antibiotics. FEMS microbiology letters 123, 11-18.
120 References
Jung, Y.J., LaCourse, R., Ryan, L., and North, R.J. (2002). Virulent but not avirulent Mycobacterium tuberculosis can evade the growth inhibitory action of a T helper 1-dependent, nitric oxide Synthase 2-independent defense in mice. The Journal of experimental medicine 196, 991-998. Kallenius, G., Koivula, T., Ghebremichael, S., Hoffner, S.E., Norberg, R., Svensson, E., Dias, F., Marklund, B.I., and Svenson, S.B. (1999). Evolution and clonal traits of Mycobacterium tuberculosis complex in Guinea-Bissau. Journal of clinical microbiology 37, 3872-3878. Kamerbeek, J., Schouls, L., Kolk, A., van Agterveld, M., van Soolingen, D., Kuijper, S., Bunschoten, A., Molhuizen, H., Shaw, R., Goyal, M., et al. (1997). Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. Journal of clinical microbiology 35, 907-914. Kang, J., and Blaser, M.J. (2006). Bacterial populations as perfect gases: genomic integrity and diversification tensions in Helicobacter pylori. Nature reviews Microbiology 4, 826-836. Kang, P.B., Azad, A.K., Torrelles, J.B., Kaufman, T.M., Beharka, A., Tibesar, E., DesJardin, L.E., and Schlesinger, L.S. (2005). The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis. The Journal of experimental medicine 202, 987-999. Kato-Maeda, M., Metcalfe, J.Z., and Flores, L. (2011). Genotyping of Mycobacterium tuberculosis: application in epidemiologic studies. Future microbiology 6, 203-216. Kato-Maeda, M., Shanley, C.A., Ackart, D., Jarlsberg, L.G., Shang, S., Obregon-Henao, A., Harton, M., Basaraba, R.J., Henao-Tamayo, M., Barrozo, J.C., et al. (2012). Beijing Sublineages of Mycobacterium tuberculosis Differ in Pathogenicity in the Guinea Pig. Clinical and vaccine immunology : CVI 19, 1227-1237. Kaufmann, S.H. (2011). Fact and fiction in tuberculosis vaccine research: 10 years later. The Lancet infectious diseases 11, 633-640. Kaufmann, S.H., and McMichael, A.J. (2005). Annulling a dangerous liaison: vaccination strategies against AIDS and tuberculosis. Nature medicine 11, S33-44. Kaur, D., Guerin, M.E., Skovierova, H., Brennan, P.J., and Jackson, M. (2009). Chapter 2: Biogenesis of the cell wall and other glycoconjugates of Mycobacterium tuberculosis. Advances in applied microbiology 69, 23-78. Keren, I., Minami, S., Rubin, E., and Lewis, K. (2011). Characterization and transcriptome analysis of Mycobacterium tuberculosis persisters. mBio 2, e00100-00111. Koch, R. (1882). Die Aetiogie der Tuberculose. Berl Klin Wochenschr 19, 221–230. Koch, R. (1982). Classics in infectious diseases. The etiology of tuberculosis: Robert Koch. Berlin, Germany 1882. Reviews of infectious diseases 4, 1270-1274. Kohanski, M.A., Dwyer, D.J., Hayete, B., Lawrence, C.A., and Collins, J.J. (2007). A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130, 797-810. Kremer, K., Au, B.K., Yip, P.C., Skuce, R., Supply, P., Kam, K.M., and van Soolingen, D. (2005). Use of variable-number tandem-repeat typing to differentiate Mycobacterium tuberculosis Beijing family isolates from Hong Kong and comparison with IS6110 restriction fragment length polymorphism typing and spoligotyping. Journal of clinical microbiology 43, 314-320. Kremer, K., Glynn, J.R., Lillebaek, T., Niemann, S., Kurepina, N.E., Kreiswirth, B.N., Bifani, P.J., and van Soolingen, D. (2004). Definition of the Beijing/W lineage of Mycobacterium tuberculosis on the basis of genetic markers. Journal of clinical microbiology 42, 4040-4049. Kremer, K., van-der-Werf, M.J., Au, B.K., Anh, D.D., Kam, K.M., van-Doorn, H.R., Borgdorff, M.W., and van-Soolingen, D. (2009). Vaccine-induced immunity circumvented by typical Mycobacterium tuberculosis Beijing strains. Emerging infectious diseases 15, 335-339. Kurepina, N.E., Sreevatsan, S., Plikaytis, B.B., Bifani, P.J., Connell, N.D., Donnelly, R.J., van Sooligen, D., Musser, J.M., and Kreiswirth, B.N. (1998). Characterization of the phylogenetic distribution and chromosomal insertion sites of five IS6110 elements in Mycobacterium tuberculosis: non-random integration in the dnaA-dnaN region. Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 79, 31-42.
121 References
Kurthkoti, K., Kumar, P., Jain, R., and Varshney, U. (2008). Important role of the nucleotide excision repair pathway in Mycobacterium smegmatis in conferring protection against commonly encountered DNA-damaging agents. Microbiology 154, 2776-2785. Kurthkoti, K., Srinath, T., Kumar, P., Malshetty, V.S., Sang, P.B., Jain, R., Manjunath, R., and Varshney, U. (2010). A distinct physiological role of MutY in mutation prevention in mycobacteria. Microbiology 156, 88-93. Lamhamedi-Cherradi, S., de Chastellier, C., and Casanova, J.L. (1999). Growth of Mycobacterium bovis, Bacille Calmette-Guerin, within human monocytes-macrophages cultured in serum-free medium. Journal of immunological methods 225, 75-86. Lamichhane, G., Tyagi, S., and Bishai, W.R. (2005). Designer arrays for defined mutant analysis to detect genes essential for survival of Mycobacterium tuberculosis in mouse lungs. Infection and immunity 73, 2533-2540. Lari, N., Rindi, L., Bonanni, D., Tortoli, E., and Garzelli, C. (2006). Mutations in mutT genes of Mycobacterium tuberculosis isolates of Beijing genotype. Journal of medical microbiology 55, 599-603. Lee, H.M., Shin, D.M., Kim, K.K., Lee, J.S., Paik, T.H., and Jo, E.K. (2009a). Roles of reactive oxygen species in CXCL8 and CCL2 expression in response to the 30-kDa antigen of Mycobacterium tuberculosis. Journal of clinical immunology 29, 46-56. Lee, M.H., Pascopella, L., Jacobs, W.R., Jr., and Hatfull, G.F. (1991). Site-specific integration of mycobacteriophage L5: integration-proficient vectors for Mycobacterium smegmatis, Mycobacterium tuberculosis, and bacille Calmette-Guerin. Proceedings of the National Academy of Sciences of the United States of America 88, 3111-3115. Lee, W.L., Gold, B., Darby, C., Brot, N., Jiang, X., de Carvalho, L.P., Wellner, D., St John, G., Jacobs, W.R., Jr., and Nathan, C. (2009b). Mycobacterium tuberculosis expresses methionine sulphoxide reductases A and B that protect from killing by nitrite and hypochlorite. Molecular microbiology 71, 583-593. Leemans, J.C., Juffermans, N.P., Florquin, S., van Rooijen, N., Vervoordeldonk, M.J., Verbon, A., van Deventer, S.J., and van der Poll, T. (2001). Depletion of alveolar macrophages exerts protective effects in pulmonary tuberculosis in mice. Journal of immunology 166, 4604-4611. Leemans, J.C., Thepen, T., Weijer, S., Florquin, S., van Rooijen, N., van de Winkel, J.G., and van der Poll, T. (2005). Macrophages play a dual role during pulmonary tuberculosis in mice. The Journal of infectious diseases 191, 65-74. Levy-Frebault, V.V., and Portaels, F. (1992). Proposed minimal standards for the genus Mycobacterium and for description of new slowly growing Mycobacterium species. International journal of systematic bacteriology 42, 315-323. Li, Q., Whalen, C.C., Albert, J.M., Larkin, R., Zukowski, L., Cave, M.D., and Silver, R.F. (2002). Differences in rate and variability of intracellular growth of a panel of Mycobacterium tuberculosis clinical isolates within a human monocyte model. Infection and immunity 70, 6489-6493. Li, Y., and He, Z.G. (2012). The mycobacterial LysR-type regulator OxyS responds to oxidative stress and negatively regulates expression of the catalase-peroxidase gene. PloS one 7, e30186. Little, J.W. (1982). Control of the SOS regulatory system by the level of RecA protease. Biochimie 64, 585-589. Lopez, B., Aguilar, D., Orozco, H., Burger, M., Espitia, C., Ritacco, V., Barrera, L., Kremer, K., Hernandez-Pando, R., Huygen, K., et al. (2003). A marked difference in pathogenesis and immune response induced by different Mycobacterium tuberculosis genotypes. Clinical and experimental immunology 133, 30-37. MacGurn, J.A., and Cox, J.S. (2007). A genetic screen for Mycobacterium tuberculosis mutants defective for phagosome maturation arrest identifies components of the ESX-1 secretion system. Infection and immunity 75, 2668-2678. MacMicking, J.D., North, R.J., LaCourse, R., Mudgett, J.S., Shah, S.K., and Nathan, C.F. (1997). Identification of nitric oxide synthase as a protective locus against tuberculosis. Proceedings of the National Academy of Sciences of the United States of America 94, 5243-5248. Maddocks, S.E., and Oyston, P.C. (2008). Structure and function of the LysR-type transcriptional regulator (LTTR) family proteins. Microbiology 154, 3609-3623.
122 References
Maglione, P.J., Xu, J., Casadevall, A., and Chan, J. (2008). Fc gamma receptors regulate immune activation and susceptibility during Mycobacterium tuberculosis infection. Journal of immunology 180, 3329-3338. Malaga, W., Constant, P., Euphrasie, D., Cataldi, A., Daffe, M., Reyrat, J.M., and Guilhot, C. (2008). Deciphering the genetic bases of the structural diversity of phenolic glycolipids in strains of the Mycobacterium tuberculosis complex. The Journal of biological chemistry 283, 15177-15184. Malik, Z.A., Thompson, C.R., Hashimi, S., Porter, B., Iyer, S.S., and Kusner, D.J. (2003). Cutting edge: Mycobacterium tuberculosis blocks Ca2+ signaling and phagosome maturation in human macrophages via specific inhibition of sphingosine kinase. Journal of immunology 170, 2811-2815. Malm, S., Tiffert, Y., Micklinghoff, J., Schultze, S., Joost, I., Weber, I., Horst, S., Ackermann, B., Schmidt, M., Wohlleben, W., et al. (2009). The roles of the nitrate reductase NarGHJI, the nitrite reductase NirBD and the response regulator GlnR in nitrate assimilation of Mycobacterium tuberculosis. Microbiology 155, 1332-1339. Manca, C., Paul, S., Barry, C.E., 3rd, Freedman, V.H., and Kaplan, G. (1999). Mycobacterium tuberculosis catalase and peroxidase activities and resistance to oxidative killing in human monocytes in vitro. Infection and immunity 67, 74-79. Manganelli, R., Voskuil, M.I., Schoolnik, G.K., Dubnau, E., Gomez, M., and Smith, I. (2002). Role of the extracytoplasmic-function sigma factor sigma(H) in Mycobacterium tuberculosis global gene expression. Molecular microbiology 45, 365-374. Mange, P.F. (1992). Hansen and his discovery of Mycobacterium leprae. New Jersey medicine : the journal of the Medical Society of New Jersey 89, 118-121. Master, S.S., Springer, B., Sander, P., Boettger, E.C., Deretic, V., and Timmins, G.S. (2002). Oxidative stress response genes in Mycobacterium tuberculosis: role of ahpC in resistance to peroxynitrite and stage-specific survival in macrophages. Microbiology 148, 3139-3144. McAdam, R.A., Quan, S., Smith, D.A., Bardarov, S., Betts, J.C., Cook, F.C., Hooker, E.U., Lewis, A.P., Woollard, P., Everett, M.J., et al. (2002). Characterization of a Mycobacterium tuberculosis H37Rv transposon library reveals insertions in 351 ORFs and mutants with altered virulence. Microbiology 148, 2975-2986. McGuire, A.M., Weiner, B., Park, S.T., Wapinski, I., Raman, S., Dolganov, G., Peterson, M., Riley, R., Zucker, J., Abeel, T., et al. (2012). Comparative analysis of Mycobacterium and related Actinomycetes yields insight into the evolution of Mycobacterium tuberculosis pathogenesis. BMC genomics 13, 120. McKinney, J.D., Honer zu Bentrup, K., Munoz-Elias, E.J., Miczak, A., Chen, B., Chan, W.T., Swenson, D., Sacchettini, J.C., Jacobs, W.R., Jr., and Russell, D.G. (2000). Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406, 735-738. Mehra, S., and Kaushal, D. (2009). Functional genomics reveals extended roles of the Mycobacterium tuberculosis stress response factor sigmaH. Journal of bacteriology 191, 3965-3980. Michaels, M.L., and Miller, J.H. (1992). The GO system protects organisms from the mutagenic effect of the spontaneous lesion 8-hydroxyguanine (7,8-dihydro-8-oxoguanine). Journal of bacteriology 174, 6321-6325. Miller, J.L., Velmurugan, K., Cowan, M.J., and Briken, V. (2010). The type I NADH dehydrogenase of Mycobacterium tuberculosis counters phagosomal NOX2 activity to inhibit TNF-alpha-mediated host cell apoptosis. PLoS pathogens 6, e1000864. Minakami, R., and Sumimotoa, H. (2006). Phagocytosis-coupled activation of the superoxide-producing phagocyte oxidase, a member of the NADPH oxidase (nox) family. International journal of hematology 84, 193-198. Mizrahi, V., and Andersen, S.J. (1998). DNA repair in Mycobacterium tuberculosis. What have we learnt from the genome sequence? Molecular microbiology 29, 1331-1339. Mokrousov, I., Jiao, W.W., Sun, G.Z., Liu, J.W., Valcheva, V., Li, M., Narvskaya, O., and Shen, A.D. (2006). Evolution of drug resistance in different sublineages of Mycobacterium tuberculosis Beijing genotype. Antimicrobial agents and chemotherapy 50, 2820-2823.
123 References
Moreland, N.J., Charlier, C., Dingley, A.J., Baker, E.N., and Lott, J.S. (2009). Making sense of a missense mutation: characterization of MutT2, a Nudix hydrolase from Mycobacterium tuberculosis, and the G58R mutant encoded in W-Beijing strains of M. tuberculosis. Biochemistry 48, 699-708. Morimatsu, K., and Kowalczykowski, S.C. (2003). RecFOR proteins load RecA protein onto gapped DNA to accelerate DNA strand exchange: a universal step of recombinational repair. Mol Cell 11, 1337-1347. Morlock, G.P., Plikaytis, B.B., and Crawford, J.T. (2000). Characterization of spontaneous, In vitro-selected, rifampin-resistant mutants of Mycobacterium tuberculosis strain H37Rv. Antimicrobial agents and chemotherapy 44, 3298-3301. Mostowy, S., Inwald, J., Gordon, S., Martin, C., Warren, R., Kremer, K., Cousins, D., and Behr, M.A. (2005). Revisiting the evolution of Mycobacterium bovis. Journal of bacteriology 187, 6386-6395. Mukherjee, P., Sureka, K., Datta, P., Hossain, T., Barik, S., Das, K.P., Kundu, M., and Basu, J. (2009). Novel role of Wag31 in protection of mycobacteria under oxidative stress. Molecular microbiology 73, 103-119. Namouchi, A., Didelot, X., Schock, U., Gicquel, B., and Rocha, E.P. (2012). After the bottleneck: Genome-wide diversification of the Mycobacterium tuberculosis complex by mutation, recombination, and natural selection. Genome research 22, 721-734. Ng, V.H., Cox, J.S., Sousa, A.O., MacMicking, J.D., and McKinney, J.D. (2004). Role of KatG catalase-peroxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst. Molecular microbiology 52, 1291-1302. Nguyen, L., and Thompson, C.J. (2006). Foundations of antibiotic resistance in bacterial physiology: the mycobacterial paradigm. Trends in microbiology 14, 304-312. Nicholson, S., Bonecini-Almeida Mda, G., Lapa e Silva, J.R., Nathan, C., Xie, Q.W., Mumford, R., Weidner, J.R., Calaycay, J., Geng, J., Boechat, N., et al. (1996). Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis. The Journal of experimental medicine 183, 2293-2302. Nickel, D., Busch, M., Mayer, D., Hagemann, B., Knoll, V., and Stenger, S. (2012). Hypoxia triggers the expression of human beta defensin 2 and antimicrobial activity against Mycobacterium tuberculosis in human macrophages. Journal of immunology 188, 4001-4007. Nicol, M.P., and Wilkinson, R.J. (2008). The clinical consequences of strain diversity in Mycobacterium tuberculosis. Transactions of the Royal Society of Tropical Medicine and Hygiene 102, 955-965. Niederweis, M., Danilchanka, O., Huff, J., Hoffmann, C., and Engelhardt, H. (2010). Mycobacterial outer membranes: in search of proteins. Trends in microbiology 18, 109-116. Nigou, J., Zelle-Rieser, C., Gilleron, M., Thurnher, M., and Puzo, G. (2001). Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: evidence for a negative signal delivered through the mannose receptor. Journal of immunology 166, 7477-7485. Nikaido, H. (2001). Preventing drug access to targets: cell surface permeability barriers and active efflux in bacteria. Seminars in cell & developmental biology 12, 215-223. Nozaki, Y., Hasegawa, Y., Ichiyama, S., Nakashima, I., and Shimokata, K. (1997). Mechanism of nitric oxide-dependent killing of Mycobacterium bovis BCG in human alveolar macrophages. Infection and immunity 65, 3644-3647. O'Brien, L., Carmichael, J., Lowrie, D.B., and Andrew, P.W. (1994). Strains of Mycobacterium tuberculosis differ in susceptibility to reactive nitrogen intermediates in vitro. Infection and immunity 62, 5187-5190. O'Brien, P.J., and Ellenberger, T. (2004). The Escherichia coli 3-methyladenine DNA glycosylase AlkA has a remarkably versatile active site. The Journal of biological chemistry 279, 26876-26884. O'Rourke, E.J., Chevalier, C., Pinto, A.V., Thiberge, J.M., Ielpi, L., Labigne, A., and Radicella, J.P. (2003). Pathogen DNA as target for host-generated oxidative stress: role for repair of bacterial DNA damage in Helicobacter pylori colonization. Proceedings of the National Academy of Sciences of the United States of America 100, 2789-2794. O'Sullivan, D.M., McHugh, T.D., and Gillespie, S.H. (2005). Analysis of rpoB and pncA mutations in the published literature: an insight into the role of oxidative stress in Mycobacterium tuberculosis evolution? The Journal of antimicrobial chemotherapy 55, 674-679.
124 References
O'Toole, R. (2010). Experimental models used to study human tuberculosis. Advances in applied microbiology 71, 75-89. Ortalo-Magne, A., Dupont, M.A., Lemassu, A., Andersen, A.B., Gounon, P., and Daffe, M. (1995). Molecular composition of the outermost capsular material of the tubercle bacillus. Microbiology 141 ( Pt 7), 1609-1620. Pagan-Ramos, E., Song, J., McFalone, M., Mudd, M.H., and Deretic, V. (1998). Oxidative stress response and characterization of the oxyR-ahpC and furA-katG loci in Mycobacterium marinum. Journal of bacteriology 180, 4856-4864. Palanisamy, G.S., DuTeau, N., Eisenach, K.D., Cave, D.M., Theus, S.A., Kreiswirth, B.N., Basaraba, R.J., and Orme, I.M. (2009). Clinical strains of Mycobacterium tuberculosis display a wide range of virulence in guinea pigs. Tuberculosis 89, 203-209. Palomino, J.C. (2012). Current developments and future perspectives for TB diagnostics. Future microbiology 7, 59-71. Parish, T. (2003). Starvation survival response of Mycobacterium tuberculosis. Journal of bacteriology 185, 6702-6706. Parish, T., and Stoker, N.G. (1998). Electroporation of mycobacteria. Methods Mol Biol 101, 129-144. Parwati, I., van Crevel, R., and van Soolingen, D. (2010). Possible underlying mechanisms for successful emergence of the Mycobacterium tuberculosis Beijing genotype strains. The Lancet infectious diseases 10, 103-111. Pathak, S.K., Basu, S., Basu, K.K., Banerjee, A., Pathak, S., Bhattacharyya, A., Kaisho, T., Kundu, M., and Basu, J. (2007). Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages. Nature immunology 8, 610-618. Perdigao, J., Macedo, R., Joao, I., Fernandes, E., Brum, L., and Portugal, I. (2008). Multidrug-resistant tuberculosis in Lisbon, Portugal: a molecular epidemiological perspective. Microb Drug Resist 14, 133-143. Perdigao, J., Macedo, R., Silva, C., Pinto, C., Furtado, C., Brum, L., and Portugal, I. (2011). Tuberculosis drug-resistance in Lisbon, Portugal: a 6-year overview. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 17, 1397-1402. Perez, E., Samper, S., Bordas, Y., Guilhot, C., Gicquel, B., and Martin, C. (2001). An essential role for phoP in Mycobacterium tuberculosis virulence. Molecular microbiology 41, 179-187. Pethe, K., Swenson, D.L., Alonso, S., Anderson, J., Wang, C., and Russell, D.G. (2004). Isolation of Mycobacterium tuberculosis mutants defective in the arrest of phagosome maturation. Proceedings of the National Academy of Sciences of the United States of America 101, 13642-13647. Philips, J.A. (2008). Mycobacterial manipulation of vacuolar sorting. Cellular microbiology 10, 2408-2415. Piddington, D.L., Fang, F.C., Laessig, T., Cooper, A.M., Orme, I.M., and Buchmeier, N.A. (2001). Cu,Zn superoxide dismutase of Mycobacterium tuberculosis contributes to survival in activated macrophages that are generating an oxidative burst. Infection and immunity 69, 4980-4987. Pitarque, S., Larrouy-Maumus, G., Payre, B., Jackson, M., Puzo, G., and Nigou, J. (2008). The immunomodulatory lipoglycans, lipoarabinomannan and lipomannan, are exposed at the mycobacterial cell surface. Tuberculosis 88, 560-565. Portugal, I., Covas, M.J., Brum, L., Viveiros, M., Ferrinho, P., Moniz-Pereira, J., and David, H. (1999). Outbreak of multiple drug-resistant tuberculosis in Lisbon: detection by restriction fragment length polymorphism analysis. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 3, 207-213. Rachman, H., Strong, M., Ulrichs, T., Grode, L., Schuchhardt, J., Mollenkopf, H., Kosmiadi, G.A., Eisenberg, D., and Kaufmann, S.H. (2006). Unique transcriptome signature of Mycobacterium tuberculosis in pulmonary tuberculosis. Infection and immunity 74, 1233-1242. Ramachandra, L., Noss, E., Boom, W.H., and Harding, C.V. (2001). Processing of Mycobacterium tuberculosis antigen 85B involves intraphagosomal formation of peptide-major histocompatibility
125 References
complex II complexes and is inhibited by live bacilli that decrease phagosome maturation. The Journal of experimental medicine 194, 1421-1432. Raman, S., Song, T., Puyang, X., Bardarov, S., Jacobs, W.R., Jr., and Husson, R.N. (2001). The alternative sigma factor SigH regulates major components of oxidative and heat stress responses in Mycobacterium tuberculosis. Journal of bacteriology 183, 6119-6125. Ramon-Garcia, S., Martin, C., Thompson, C.J., and Ainsa, J.A. (2009). Role of the Mycobacterium tuberculosis P55 efflux pump in intrinsic drug resistance, oxidative stress responses, and growth. Antimicrobial agents and chemotherapy 53, 3675-3682. Rand, L., Hinds, J., Springer, B., Sander, P., Buxton, R.S., and Davis, E.O. (2003). The majority of inducible DNA repair genes in Mycobacterium tuberculosis are induced independently of RecA. Molecular microbiology 50, 1031-1042. Rauch, P.J., Palmen, R., Burds, A.A., Gregg-Jolly, L.A., van der Zee, J.R., and Hellingwerf, K.J. (1996). The expression of the Acinetobacter calcoaceticus recA gene increases in response to DNA damage independently of RecA and of development of competence for natural transformation. Microbiology 142 ( Pt 4), 1025-1032. Reed, M.B., Domenech, P., Manca, C., Su, H., Barczak, A.K., Kreiswirth, B.N., Kaplan, G., and Barry, C.E., 3rd (2004). A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431, 84-87. Reed, M.B., Gagneux, S., Deriemer, K., Small, P.M., and Barry, C.E., 3rd (2007). The W-Beijing lineage of Mycobacterium tuberculosis overproduces triglycerides and has the DosR dormancy regulon constitutively upregulated. Journal of bacteriology 189, 2583-2589. Reiling, N., Holscher, C., Fehrenbach, A., Kroger, S., Kirschning, C.J., Goyert, S., and Ehlers, S. (2002). Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. Journal of immunology 169, 3480-3484. Rengarajan, J., Bloom, B.R., and Rubin, E.J. (2005). Genome-wide requirements for Mycobacterium tuberculosis adaptation and survival in macrophages. Proceedings of the National Academy of Sciences of the United States of America 102, 8327-8332. Rhee, K.Y., Erdjument-Bromage, H., Tempst, P., and Nathan, C.F. (2005). S-nitroso proteome of Mycobacterium tuberculosis: Enzymes of intermediary metabolism and antioxidant defense. Proceedings of the National Academy of Sciences of the United States of America 102, 467-472. Rindi, L., Lari, N., Cuccu, B., and Garzelli, C. (2009). Evolutionary pathway of the Beijing lineage of Mycobacterium tuberculosis based on genomic deletions and mutT genes polymorphisms. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 9, 48-53. Rodriguez, G.M., Voskuil, M.I., Gold, B., Schoolnik, G.K., and Smith, I. (2002). ideR, An essential gene in mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response. Infection and immunity 70, 3371-3381. Rohde, K.H., Abramovitch, R.B., and Russell, D.G. (2007). Mycobacterium tuberculosis invasion of macrophages: linking bacterial gene expression to environmental cues. Cell host & microbe 2, 352-364. Rosas-Magallanes, V., Stadthagen-Gomez, G., Rauzier, J., Barreiro, L.B., Tailleux, L., Boudou, F., Griffin, R., Nigou, J., Jackson, M., Gicquel, B., et al. (2007). Signature-tagged transposon mutagenesis identifies novel Mycobacterium tuberculosis genes involved in the parasitism of human macrophages. Infection and immunity 75, 504-507. Rossi, F., Khanduja, J.S., Bortoluzzi, A., Houghton, J., Sander, P., Guthlein, C., Davis, E.O., Springer, B., Bottger, E.C., Relini, A., et al. (2011). The biological and structural characterization of Mycobacterium tuberculosis UvrA provides novel insights into its mechanism of action. Nucleic Acids Res 39, 7316-7328. Russell, D.G. (2007). Who puts the tubercle in tuberculosis? Nature reviews Microbiology 5, 39-47. Ryffel, B., Fremond, C., Jacobs, M., Parida, S., Botha, T., Schnyder, B., and Quesniaux, V. (2005). Innate immunity to mycobacterial infection in mice: critical role for toll-like receptors. Tuberculosis 85, 395-405.
126 References
Sala, C., Forti, F., Di Florio, E., Canneva, F., Milano, A., Riccardi, G., and Ghisotti, D. (2003). Mycobacterium tuberculosis FurA autoregulates its own expression. Journal of bacteriology 185, 5357-5362. Sani, M., Houben, E.N., Geurtsen, J., Pierson, J., de Punder, K., van Zon, M., Wever, B., Piersma, S.R., Jimenez, C.R., Daffe, M., et al. (2010). Direct visualization by cryo-EM of the mycobacterial capsular layer: a labile structure containing ESX-1-secreted proteins. PLoS pathogens 6, e1000794. Sarkar, S., and Suresh, M.R. (2011). An overview of tuberculosis chemotherapy - a literature review. Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 14, 148-161. Sassetti, C.M., and Rubin, E.J. (2003). Genetic requirements for mycobacterial survival during infection. Proceedings of the National Academy of Sciences of the United States of America 100, 12989-12994. Schlesinger, L.S. (1993). Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to complement receptors. Journal of immunology 150, 2920-2930. Schnappinger, D., Ehrt, S., Voskuil, M.I., Liu, Y., Mangan, J.A., Monahan, I.M., Dolganov, G., Efron, B., Butcher, P.D., Nathan, C., et al. (2003). Transcriptional Adaptation of Mycobacterium tuberculosis within Macrophages: Insights into the Phagosomal Environment. The Journal of experimental medicine 198, 693-704. Schurch, A.C., Kremer, K., Warren, R.M., Hung, N.V., Zhao, Y., Wan, K., Boeree, M.J., Siezen, R.J., Smith, N.H., and van Soolingen, D. (2011). Mutations in the regulatory network underlie the recent clonal expansion of a dominant subclone of the Mycobacterium tuberculosis Beijing genotype. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 11, 587-597. Seeberg, E., Eide, L., and Bjoras, M. (1995). The base excision repair pathway. Trends Biochem Sci 20, 391-397. Senaratne, R.H., De Silva, A.D., Williams, S.J., Mougous, J.D., Reader, J.R., Zhang, T., Chan, S., Sidders, B., Lee, D.H., Chan, J., et al. (2006). 5'-Adenosinephosphosulphate reductase (CysH) protects Mycobacterium tuberculosis against free radicals during chronic infection phase in mice. Molecular microbiology 59, 1744-1753. Shibutani, S., Takeshita, M., and Grollman, A.P. (1991). Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature 349, 431-434. Shin, D.M., Yang, C.S., Lee, J.Y., Lee, S.J., Choi, H.H., Lee, H.M., Yuk, J.M., Harding, C.V., and Jo, E.K. (2008). Mycobacterium tuberculosis lipoprotein-induced association of TLR2 with protein kinase C zeta in lipid rafts contributes to reactive oxygen species-dependent inflammatory signalling in macrophages. Cellular microbiology 10, 1893-1905. Shin, D.M., Yuk, J.M., Lee, H.M., Lee, S.H., Son, J.W., Harding, C.V., Kim, J.M., Modlin, R.L., and Jo, E.K. (2010). Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling. Cellular microbiology 12, 1648-1665. Shinnick, T.M., and Good, R.C. (1994). Mycobacterial taxonomy. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 13, 884-901. Shuman, S., and Glickman, M.S. (2007). Bacterial DNA repair by non-homologous end joining. Nature reviews Microbiology 5, 852-861. Singleton, M.R., Dillingham, M.S., Gaudier, M., Kowalczykowski, S.C., and Wigley, D.B. (2004). Crystal structure of RecBCD enzyme reveals a machine for processing DNA breaks. Nature 432, 187-193. Sinha, K.M., Stephanou, N.C., Gao, F., Glickman, M.S., and Shuman, S. (2007). Mycobacterial UvrD1 is a Ku-dependent DNA helicase that plays a role in multiple DNA repair events, including double-strand break repair. The Journal of biological chemistry 282, 15114-15125. Slupphaug, G., Kavli, B., and Krokan, H.E. (2003). The interacting pathways for prevention and repair of oxidative DNA damage. Mutation research 531, 231-251.
127 References
Sly, L.M., Lopez, M., Nauseef, W.M., and Reiner, N.E. (2001). 1alpha,25-Dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phosphatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase. The Journal of biological chemistry 276, 35482-35493. Smith, N.H., Kremer, K., Inwald, J., Dale, J., Driscoll, J.R., Gordon, S.V., van Soolingen, D., Hewinson, R.G., and Smith, J.M. (2006). Ecotypes of the Mycobacterium tuberculosis complex. Journal of theoretical biology 239, 220-225. Sohaskey, C.D., and Wayne, L.G. (2003). Role of narK2X and narGHJI in hypoxic upregulation of nitrate reduction by Mycobacterium tuberculosis. Journal of bacteriology 185, 7247-7256. Springer, B., Master, S., Sander, P., Zahrt, T., McFalone, M., Song, J., Papavinasasundaram, K.G., Colston, M.J., Boettger, E., and Deretic, V. (2001). Silencing of oxidative stress response in Mycobacterium tuberculosis: expression patterns of ahpC in virulent and avirulent strains and effect of ahpC inactivation. Infection and immunity 69, 5967-5973. Sreevatsan, S., Pan, X., Stockbauer, K.E., Connell, N.D., Kreiswirth, B.N., Whittam, T.S., and Musser, J.M. (1997). Restricted structural gene polymorphism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination. Proceedings of the National Academy of Sciences of the United States of America 94, 9869-9874. Stahl, D.A., and Urbance, J.W. (1990). The division between fast- and slow-growing species corresponds to natural relationships among the mycobacteria. Journal of bacteriology 172, 116-124. Stallings, C.L., Stephanou, N.C., Chu, L., Hochschild, A., Nickels, B.E., and Glickman, M.S. (2009). CarD is an essential regulator of rRNA transcription required for Mycobacterium tuberculosis persistence. Cell 138, 146-159. Stephenson, J.D., and Shepherd, V.L. (1987). Purification of the human alveolar macrophage mannose receptor. Biochemical and biophysical research communications 148, 883-889. Storz, G., and Imlay, J.A. (1999). Oxidative stress. Current opinion in microbiology 2, 188-194. Sturgill-Koszycki, S., Schlesinger, P.H., Chakraborty, P., Haddix, P.L., Collins, H.L., Fok, A.K., Allen, R.D., Gluck, S.L., Heuser, J., and Russell, D.G. (1994). Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science 263, 678-681. Sugawara, I., Yamada, H., Li, C., Mizuno, S., Takeuchi, O., and Akira, S. (2003). Mycobacterial infection in TLR2 and TLR6 knockout mice. Microbiology and immunology 47, 327-336. Sun, J., Wang, X., Lau, A., Liao, T.Y., Bucci, C., and Hmama, Z. (2010). Mycobacterial nucleoside diphosphate kinase blocks phagosome maturation in murine RAW 264.7 macrophages. PloS one 5, e8769. Supply, P., Mazars, E., Lesjean, S., Vincent, V., Gicquel, B., and Locht, C. (2000). Variable human minisatellite-like regions in the Mycobacterium tuberculosis genome. Molecular microbiology 36, 762-771. Supply, P., Warren, R.M., Banuls, A.L., Lesjean, S., Van Der Spuy, G.D., Lewis, L.A., Tibayrenc, M., Van Helden, P.D., and Locht, C. (2003). Linkage disequilibrium between minisatellite loci supports clonal evolution of Mycobacterium tuberculosis in a high tuberculosis incidence area. Molecular microbiology 47, 529-538. Swaminathan, S., Padmapriyadarsini, C., and Narendran, G. (2010). HIV-associated tuberculosis: clinical update. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 50, 1377-1386. Taddei, F., Radman, M., Maynard-Smith, J., Toupance, B., Gouyon, P.H., and Godelle, B. (1997). Role of mutator alleles in adaptive evolution. Nature 387, 700-702. Tailleux, L., Pham-Thi, N., Bergeron-Lafaurie, A., Herrmann, J.L., Charles, P., Schwartz, O., Scheinmann, P., Lagrange, P.H., de Blic, J., Tazi, A., et al. (2005). DC-SIGN induction in alveolar macrophages defines privileged target host cells for mycobacteria in patients with tuberculosis. PLoS medicine 2, e381. Tailleux, L., Schwartz, O., Herrmann, J.L., Pivert, E., Jackson, M., Amara, A., Legres, L., Dreher, D., Nicod, L.P., Gluckman, J.C., et al. (2003). DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. The Journal of experimental medicine 197, 121-127. Tailleux, L., Waddell, S.J., Pelizzola, M., Mortellaro, A., Withers, M., Tanne, A., Castagnoli, P.R., Gicquel, B., Stoker, N.G., Butcher, P.D., et al. (2008). Probing host pathogen cross-talk by transcriptional profiling
128 References
of both Mycobacterium tuberculosis and infected human dendritic cells and macrophages. PloS one 3, e1403. Tan, M.P., Sequeira, P., Lin, W.W., Phong, W.Y., Cliff, P., Ng, S.H., Lee, B.H., Camacho, L., Schnappinger, D., Ehrt, S., et al. (2010). Nitrate respiration protects hypoxic Mycobacterium tuberculosis against acid- and reactive nitrogen species stresses. PloS one 5, e13356. Tanne, A., Ma, B., Boudou, F., Tailleux, L., Botella, H., Badell, E., Levillain, F., Taylor, M.E., Drickamer, K., Nigou, J., et al. (2009). A murine DC-SIGN homologue contributes to early host defense against Mycobacterium tuberculosis. The Journal of experimental medicine 206, 2205-2220. Taverna, P., and Sedgwick, B. (1996). Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli. Journal of bacteriology 178, 5105-5111. Tekaia, F., Gordon, S.V., Garnier, T., Brosch, R., Barrell, B.G., and Cole, S.T. (1999). Analysis of the proteome of Mycobacterium tuberculosis in silico. Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 79, 329-342. Tenaillon, O., Toupance, B., Le Nagard, H., Taddei, F., and Godelle, B. (1999). Mutators, population size, adaptive landscape and the adaptation of asexual populations of bacteria. Genetics 152, 485-493. Theus, S., Eisenach, K., Fomukong, N., Silver, R.F., and Cave, M.D. (2007). Beijing family Mycobacterium tuberculosis strains differ in their intracellular growth in THP-1 macrophages. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 11, 1087-1093. Theus, S.A., Cave, M.D., and Eisenach, K.D. (2004). Activated THP-1 cells: an attractive model for the assessment of intracellular growth rates of Mycobacterium tuberculosis isolates. Infection and immunity 72, 1169-1173. Thoma-Uszynski, S., Stenger, S., Takeuchi, O., Ochoa, M.T., Engele, M., Sieling, P.A., Barnes, P.F., Rollinghoff, M., Bolcskei, P.L., Wagner, M., et al. (2001). Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291, 1544-1547. Thwaites, G., Caws, M., Chau, T.T., D'Sa, A., Lan, N.T., Huyen, M.N., Gagneux, S., Anh, P.T., Tho, D.Q., Torok, E., et al. (2008). Relationship between Mycobacterium tuberculosis genotype and the clinical phenotype of pulmonary and meningeal tuberculosis. Journal of clinical microbiology 46, 1363-1368. Tonjum, T., and Seeberg, E. (2001). Microbial fitness and genome dynamics. Trends in microbiology 9, 356-358. Torrelles, J.B., Azad, A.K., and Schlesinger, L.S. (2006). Fine discrimination in the recognition of individual species of phosphatidyl-myo-inositol mannosides from Mycobacterium tuberculosis by C-type lectin pattern recognition receptors. Journal of immunology 177, 1805-1816. Toungoussova, O.S., Caugant, D.A., Sandven, P., Mariandyshev, A.O., and Bjune, G. (2004). Impact of drug resistance on fitness of Mycobacterium tuberculosis strains of the W-Beijing genotype. FEMS immunology and medical microbiology 42, 281-290. Trunz, B.B., Fine, P., and Dye, C. (2006). Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet 367, 1173-1180. Tsenova, L., Ellison, E., Harbacheuski, R., Moreira, A.L., Kurepina, N., Reed, M.B., Mathema, B., Barry, C.E., 3rd, and Kaplan, G. (2005). Virulence of selected Mycobacterium tuberculosis clinical isolates in the rabbit model of meningitis is dependent on phenolic glycolipid produced by the bacilli. The Journal of infectious diseases 192, 98-106. Tsolaki, A.G., Gagneux, S., Pym, A.S., Goguet de la Salmoniere, Y.O., Kreiswirth, B.N., Van Soolingen, D., and Small, P.M. (2005). Genomic deletions classify the Beijing/W strains as a distinct genetic lineage of Mycobacterium tuberculosis. Journal of clinical microbiology 43, 3185-3191. Tuberculosis, E.C.A.o.N.G.G.M.a.T.f.t.E.a.C.o. (2006). Beijing/W genotype Mycobacterium tuberculosis and drug resistance. Emerging infectious diseases 12, 736-743. Tullius, M.V., Harmston, C.A., Owens, C.P., Chim, N., Morse, R.P., McMath, L.M., Iniguez, A., Kimmey, J.M., Sawaya, M.R., Whitelegge, J.P., et al. (2011). Discovery and characterization of a unique mycobacterial heme acquisition system. Proceedings of the National Academy of Sciences of the United States of America 108, 5051-5056.
129 References
Ulrichs, T., and Kaufmann, S.H. (2006). New insights into the function of granulomas in human tuberculosis. The Journal of pathology 208, 261-269. Underhill, D.M. (2007). Collaboration between the innate immune receptors dectin-1, TLRs, and Nods. Immunological reviews 219, 75-87. Valway, S.E., Sanchez, M.P., Shinnick, T.F., Orme, I., Agerton, T., Hoy, D., Jones, J.S., Westmoreland, H., and Onorato, I.M. (1998). An outbreak involving extensive transmission of a virulent strain of Mycobacterium tuberculosis. The New England journal of medicine 338, 633-639. van Embden, J.D., Cave, M.D., Crawford, J.T., Dale, J.W., Eisenach, K.D., Gicquel, B., Hermans, P., Martin, C., McAdam, R., Shinnick, T.M., et al. (1993). Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. Journal of clinical microbiology 31, 406-409. Van Soolingen, D. (2001). Molecular epidemiology of tuberculosis and other mycobacterial infections: main methodologies and achievements. Journal of internal medicine 249, 1-26. van Soolingen, D., Hoogenboezem, T., de Haas, P.E., Hermans, P.W., Koedam, M.A., Teppema, K.S., Brennan, P.J., Besra, G.S., Portaels, F., Top, J., et al. (1997). A novel pathogenic taxon of the Mycobacterium tuberculosis complex, Canetti: characterization of an exceptional isolate from Africa. International journal of systematic bacteriology 47, 1236-1245. van Soolingen, D., Qian, L., de Haas, P.E., Douglas, J.T., Traore, H., Portaels, F., Qing, H.Z., Enkhsaikan, D., Nymadawa, P., and van Embden, J.D. (1995). Predominance of a single genotype of Mycobacterium tuberculosis in countries of east Asia. Journal of clinical microbiology 33, 3234-3238. Vandal, O.H., Pierini, L.M., Schnappinger, D., Nathan, C.F., and Ehrt, S. (2008). A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium tuberculosis. Nature medicine 14, 849-854. Vandal, O.H., Roberts, J.A., Odaira, T., Schnappinger, D., Nathan, C.F., and Ehrt, S. (2009). Acid-susceptible mutants of Mycobacterium tuberculosis share hypersusceptibility to cell wall and oxidative stress and to the host environment. Journal of bacteriology 191, 625-631. Vannberg, F.O., Chapman, S.J., Khor, C.C., Tosh, K., Floyd, S., Jackson-Sillah, D., Crampin, A., Sichali, L., Bah, B., Gustafson, P., et al. (2008). CD209 genetic polymorphism and tuberculosis disease. PloS one 3, e1388. Velayati, A.A., Masjedi, M.R., Farnia, P., Tabarsi, P., Ghanavi, J., Ziazarifi, A.H., and Hoffner, S.E. (2009). Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in iran. Chest 136, 420-425. Velez, D.R., Wejse, C., Stryjewski, M.E., Abbate, E., Hulme, W.F., Myers, J.L., Estevan, R., Patillo, S.G., Olesen, R., Tacconelli, A., et al. (2010). Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans. Human genetics 127, 65-73. Venkatesh, R., Ganesh, N., Guhan, N., Reddy, M.S., Chandrasekhar, T., and Muniyappa, K. (2002). RecX protein abrogates ATP hydrolysis and strand exchange promoted by RecA: insights into negative regulation of homologous recombination. Proceedings of the National Academy of Sciences of the United States of America 99, 12091-12096. Ventura, M., Canchaya, C., Tauch, A., Chandra, G., Fitzgerald, G.F., Chater, K.F., and van Sinderen, D. (2007). Genomics of Actinobacteria: tracing the evolutionary history of an ancient phylum. Microbiology and molecular biology reviews : MMBR 71, 495-548. Vergne, I., Chua, J., and Deretic, V. (2003). Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2+/calmodulin-PI3K hVPS34 cascade. The Journal of experimental medicine 198, 653-659. Vergne, I., Chua, J., Lee, H.H., Lucas, M., Belisle, J., and Deretic, V. (2005). Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America 102, 4033-4038. Vilcheze, C., Av-Gay, Y., Attarian, R., Liu, Z., Hazbon, M.H., Colangeli, R., Chen, B., Liu, W., Alland, D., Sacchettini, J.C., et al. (2008). Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis. Molecular microbiology 69, 1316-1329.
130 References
Vollmer, W., Joris, B., Charlier, P., and Foster, S. (2008). Bacterial peptidoglycan (murein) hydrolases. FEMS microbiology reviews 32, 259-286. Voskuil, M.I., Bartek, I.L., Visconti, K., and Schoolnik, G.K. (2011). The response of mycobacterium tuberculosis to reactive oxygen and nitrogen species. Frontiers in microbiology 2, 105. Voskuil, M.I., Schnappinger, D., Rutherford, R., Liu, Y., and Schoolnik, G.K. (2004). Regulation of the Mycobacterium tuberculosis PE/PPE genes. Tuberculosis 84, 256-262. Voskuil, M.I., Schnappinger, D., Visconti, K.C., Harrell, M.I., Dolganov, G.M., Sherman, D.R., and Schoolnik, G.K. (2003). Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. The Journal of experimental medicine 198, 705-713. Walburger, A., Koul, A., Ferrari, G., Nguyen, L., Prescianotto-Baschong, C., Huygen, K., Klebl, B., Thompson, C., Bacher, G., and Pieters, J. (2004). Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 304, 1800-1804. Walker, L., and Lowrie, D.B. (1981). Killing of Mycobacterium microti by immunologically activated macrophages. Nature 293, 69-71. Walters, S.B., Dubnau, E., Kolesnikova, I., Laval, F., Daffe, M., and Smith, I. (2006). The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. Molecular microbiology 60, 312-330. Wang, C., Peyron, P., Mestre, O., Kaplan, G., van Soolingen, D., Gao, Q., Gicquel, B., and Neyrolles, O. (2010). Innate immune response to Mycobacterium tuberculosis Beijing and other genotypes. PloS one 5, e13594. Wang, C.H., Liu, C.Y., Lin, H.C., Yu, C.T., Chung, K.F., and Kuo, H.P. (1998). Increased exhaled nitric oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in alveolar macrophages. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology 11, 809-815. Wanner, R.M., Guthlein, C., Springer, B., Bottger, E.C., and Ackermann, M. (2008). Stabilization of the genome of the mismatch repair deficient Mycobacterium tuberculosis by context-dependent codon choice. BMC genomics 9, 249. Wells, C.D., Cegielski, J.P., Nelson, L.J., Laserson, K.F., Holtz, T.H., Finlay, A., Castro, K.G., and Weyer, K. (2007). HIV infection and multidrug-resistant tuberculosis: the perfect storm. The Journal of infectious diseases 196 Suppl 1, S86-107. Werle, E., Schneider, C., Renner, M., Volker, M., and Fiehn, W. (1994). Convenient single-step, one tube purification of PCR products for direct sequencing. Nucleic Acids Res 22, 4354-4355. Werngren, J., and Hoffner, S.E. (2003). Drug-susceptible Mycobacterium tuberculosis Beijing genotype does not develop mutation-conferred resistance to rifampin at an elevated rate. Journal of clinical microbiology 41, 1520-1524. Whalen, C., Horsburgh, C.R., Hom, D., Lahart, C., Simberkoff, M., and Ellner, J. (1995). Accelerated course of human immunodeficiency virus infection after tuberculosis. American journal of respiratory and critical care medicine 151, 129-135. WHO (2011). Global tuberculosis control report Williams, M.J., Kana, B.D., and Mizrahi, V. (2011). Functional analysis of molybdopterin biosynthesis in mycobacteria identifies a fused molybdopterin synthase in Mycobacterium tuberculosis. Journal of bacteriology 193, 98-106. Witkin, E.M., and Roegner-Maniscalco, V. (1992). Overproduction of DnaE protein (alpha subunit of DNA polymerase III) restores viability in a conditionally inviable Escherichia coli strain deficient in DNA polymerase I. Journal of bacteriology 174, 4166-4168. Wu, C.H., Tsai-Wu, J.J., Huang, Y.T., Lin, C.Y., Lioua, G.G., and Lee, F.J. (1998). Identification and subcellular localization of a novel Cu,Zn superoxide dismutase of Mycobacterium tuberculosis. FEBS letters 439, 192-196. Wu, K., Dong, D., Fang, H., Levillain, F., Jin, W., Mei, J., Gicquel, B., Du, Y., Wang, K., Gao, Q., et al. (2012). An interferon-related signature in the transcriptional core response of human macrophages to Mycobacterium tuberculosis infection. PloS one 7, e38367.
131 References
Yang, C.S., Shin, D.M., Kim, K.H., Lee, Z.W., Lee, C.H., Park, S.G., Bae, Y.S., and Jo, E.K. (2009). NADPH oxidase 2 interaction with TLR2 is required for efficient innate immune responses to mycobacteria via cathelicidin expression. Journal of immunology 182, 3696-3705. Yang, C.S., Shin, D.M., Lee, H.M., Son, J.W., Lee, S.J., Akira, S., Gougerot-Pocidalo, M.A., El-Benna, J., Ichijo, H., and Jo, E.K. (2008). ASK1-p38 MAPK-p47phox activation is essential for inflammatory responses during tuberculosis via TLR2-ROS signalling. Cellular microbiology 10, 741-754. Yuk, J.M., Shin, D.M., Lee, H.M., Yang, C.S., Jin, H.S., Kim, K.K., Lee, Z.W., Lee, S.H., Kim, J.M., and Jo, E.K. (2009). Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell host & microbe 6, 231-243. Zahrt, T.C., and Deretic, V. (2002). Reactive nitrogen and oxygen intermediates and bacterial defenses: unusual adaptations in Mycobacterium tuberculosis. Antioxidants & redox signaling 4, 141-159. Zhang, Y., Lathigra, R., Garbe, T., Catty, D., and Young, D. (1991). Genetic analysis of superoxide dismutase, the 23 kilodalton antigen of Mycobacterium tuberculosis. Molecular microbiology 5, 381-391. Zhang, Y., and Yew, W.W. (2009). Mechanisms of drug resistance in Mycobacterium tuberculosis. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 13, 1320-1330. Zhang, Z., Hillas, P.J., and Ortiz de Montellano, P.R. (1999). Reduction of peroxides and dinitrobenzenes by Mycobacterium tuberculosis thioredoxin and thioredoxin reductase. Archives of biochemistry and biophysics 363, 19-26. Zuber, B., Chami, M., Houssin, C., Dubochet, J., Griffiths, G., and Daffe, M. (2008). Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state. Journal of bacteriology 190, 5672-5680. Zumla, A., Abubakar, I., Raviglione, M., Hoelscher, M., Ditiu, L., McHugh, T.D., Squire, S.B., Cox, H., Ford, N., McNerney, R., et al. (2012). Drug-resistant tuberculosis--current dilemmas, unanswered questions, challenges, and priority needs. The Journal of infectious diseases 205 Suppl 2, S228-240.
Annex
134 Annex
Table A1. Description of M. tuberculosis Beijing/W strains belonging to each node found in Figure 1 and
2, and respective country of isolation.
Node Strain Origin of isolation Node Strain Origin of isolation
Bmyc1 NL25 USA Bmyc10 BE5 Singapore
ZA40 South Africa BE8 USA
Bmyc2 NL20 The Netherlands BE10 USA
CN1 China BE12 USA
CN2 China BE14 USA
CN3 China BE17 USA
CN4 China BE19 USA
CN5 China BE20 USA
CN6 China BE23 USA
CN7 China BE27 USA
CN8 China MG3 Madagascar
CN9 China MG10 Madagascar
ZA13 South Africa MG11 Madagascar
ZA42 South Africa MG21 Madagascar
ZA43 South Africa CN60 China
ZA51 South Africa CN61 China
Bmyc3 NL34 USA CN62 China
Bmyc4 NL17 USA CN63 China
BE26 USA CN64 China
CN10 China CN65 China
CN11 China CN66 China
CN12 China CN67 China
CN13 China CN68 China
CN14 China CN69 China
CN15 China CN70 China
CN16 China CN71 China
CN17 China CN72 China
CN18 China CN73 China
ZA45 South Africa CN74 China
ZA52 South Africa CN75 China
Bmyc5 NL33 USA CN76 China
Bmyc6 NL19 South Korea CN77 China
CN20 China CN78 China
CN21 China CN79 China
CN22 China CN80 China
CN23 China CN81 China
CN24 China CN82 China
CN25 China CN83 China
Bmyc7 BE3 South Korea CN84 China
Bmyc8 NL21 The Netherlands CN85 China
Bmyc9 MG9 Madagascar CN86 China
Bmyc10 NL1 Mongolia CN87 China
NL2 South Africa CN88 China
NL3 Malaysia CN89 China
NL7 Thailand CN90 China
NL18 The Netherlands CN91 China
NL23 The Netherlands CN92 China
NL24 The Netherlands CN93 China
NL31 The Netherlands CN94 China
BE1 USA CN95 China
135 Annex
Node Strain Origin of isolation Node Strain Origin of isolation
Bmyc10 CN96 China Bmyc10 CN150 China
CN97 China CN151 China
CN98 China CN153 China
CN99 China CN154 China
CN100 China CN155 China
CN101 China CN156 China
CN102 China CN157 China
CN103 China CN158 China
CN104 China CN159 China
CN105 China CN160 China
CN106 China CN161 China
CN107 China CN162 China
CN108 China CN163 China
CN109 China CN164 China
CN110 China CN165 China
CN111 China CN166 China
CN112 China CN167 China
CN113 China CN168 China
CN114 China CN169 China
CN115 China CN170 China
CN116 China CN171 China
CN117 China CN172 China
CN118 China CN173 China
CN119 China CN174 China
CN120 China CN175 China
CN121 China CN176 China
CN122 China CN177 China
CN123 China CN178 China
CN124 China CN179 China
CN125 China CN180 China
CN126 China CN181 China
CN127 China CN182 China
CN128 China ZA1 South Africa
CN129 China ZA2 South Africa
CN130 China ZA3 South Africa
CN131 China ZA4 South Africa
CN132 China ZA5 South Africa
CN133 China ZA6 South Africa
CN134 China ZA7 South Africa
CN135 China ZA8 South Africa
CN136 China ZA10 South Africa
CN137 China ZA11 South Africa
CN138 China ZA12 South Africa
CN139 China ZA15 South Africa
CN140 China ZA16 South Africa
CN141 China ZA17 South Africa
CN142 China ZA18 South Africa
CN143 China ZA20 South Africa
CN144 China ZA21 South Africa
CN145 China ZA22 South Africa
CN146 China ZA23 South Africa
CN147 China ZA24 South Africa
CN148 China ZA25 South Africa
CN149 China ZA26 South Africa
136 Annex
Node Strain Origin of isolation Node Strain Origin of isolation