Vers une théorie génétique des mycobactéries humaines Jacinta Bustamante MD, PhD Laboratory of Human Genetics of Infectious Diseases - INSERM U980 Necker-Enfants Malades Medical School, Paris, France JNI – 11 Journées Nationales d’Infectiologie Du mercredi 9 au vendredi 11 juin 2010 – Le Corum, Montpellier
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Vers une théorie génétiquedes mycobactéries humaines
Jacinta Bustamante MD, PhDLaboratory of Human Genetics of Infectious Diseases - INSERM U980
Necker-Enfants Malades Medical School, Paris, France
JNI – 11 Journées Nationales d’Infectiologie
Du mercredi 9 au vendredi 11 juin 2010 – Le Corum, Montpellier
Déclaration de conflits d’intérêts: Jacinta Bustamante MD, PhD
Laboratory of Human Genetics of Infectious Diseases - INSERM U980
Necker-Enfants Malades Medical School, Paris, France
JNI – 11 Journées Nationales d’Infectiologie
Du mercredi 9 au vendredi 11 juin 2010 – Le Corum, Montpellier
Absence de conflits d’intérêt
The genus The genus MycobacteriumMycobacterium
‘Virulent’ ‘Weakly virulent’M. tuberculosis complex > 80 species (e.g. M. avium,
M. leprae M. marinum, M. fortuitum…)
Human transmission Environmental transmission
(airborne) (water, soil, air…)
M. ulcerans (Buruli ulcer) BCG vaccine
Aquatic bug transmission? Injection transmission
Inter-individual variability in tuberculosis:the key question
Accidental
inoculation with
M. tuberculosis
251 infants
Death by year 177 infants
No sign of infection
47 infants
Various signs of infection127 infants
• The Lübeck disaster before world war II
Immunity
Microbialfactors
Exposure toMicrobe
BiologicalPhenotypes
ClinicalPhenotypes
EcologicalFactors
EpigeneticFactors
GeneticFactors
Environment
Host
Four theories of infectious diseases
0
10
20
30
40
50
60M
orta
lity
per 1
00,0
00
0--1
1--2
3--5
6--1
0
11--1
5
16--2
0
21--3
0
31--4
0
41--5
0
51--6
0
61--7
0
over
70
years
generalized TBpulmonary TB
Tuberculosis in children and adults
Ranke, K. 1910. Diagnose und Epidemiologie der Lungentuberculosedes Kindes. Archiv für Kinderheilkunde 54:279-306.
P1Born 1953No BCG vaccination10 yo: pulmonary TB34 yo: disseminated TBNow 57 yo and welloff all treatment
P2Born 1950BCG inoculation at birth3 mo: BCG-itis12 yo: BCG-itis29 yo: BCG cervical adenitisNow 60 yo and welloff all treatment
P3Born 1955BCG inoculation at birth3 mo: BCG-itisNow 55 yo and welloff all treatment
P4Born 1974 (index case, 1998)BCG inoculation at 2 years3 mo: BCG-itis21 yo: BCG abdominal adenitis24 yo: BCG cervical adenitis27 yo: BCG cervical adenitisNow 36 yo and welloff all treatment
Case reports – Kindred B
P5Born 1974BCG inoculation at birth3 mo: BCG-itisNow 36 yo and welloff all treatment
P6Born 1969BCG inoculation at birth6 mo: BCG-itis4 yo: BCG-itis39 yo: BCG-osisNow 41 yo well off alltreatment
P7Born 1974BCG inoculation at birth3 mo: BCG-itis11 yo: BCG-osis17 yo: BCG-itisNow 36 yo and well off all treatment
Cellular phenotype
Known MSMD etiologies:AD and AR: IL12B, IL12RB1, IFNGR1, IFNGR2, STAT1XR: NEMO (gene structure and function)IL-12 and IFN-γ loops…
Known XR primary immunodeficiencies:XR WAS (platelets, skin, Ig)XR (S)CID (T cell number and function)XR CGD (NBT, chemiluminescence)CD40L (expression)…
LOD
sco
reXp11.4 - Xp21.2 Xq25 - Xq26.3
Positional cloning: X-linked
Strict co-segregation of the CYBB(gp91phox, NOX2) mutation