Infection and Immunity in Autism Spectrum Disorders New Tools for Pathogen Discovery 18-19 April 2007 Institute of Medicine Washington, DC W. Ian Lipkin Columbia University and the Northeast Biodefense Center NIAID, NINDS, NHLBI, NEI, DOD, CAN PANDORA’S BOX PROJECT
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Infection and Immunity in Autism Spectrum DisordersNew Tools for Pathogen Discovery
18-19 April 2007Institute of Medicine
Washington, DC
W. Ian LipkinColumbia University and the Northeast Biodefense Center
NIAID, NINDS, NHLBI, NEI, DOD, CAN
PANDORA’S BOX PROJECT
MECHANISMS OF MICROBIAL PATHOGENESISPart I
Direct effects at infection sitereplication causes cell damagePoliovirusMotor neurons are killed, causing paralysis
toxin alters local physiologyVibrio choleracholera toxin alters ion transport in intestine, causing diarrhea
Effects distal to infection sitemicrobe produces a toxin with distant effectClostridium botulinumBotulinum toxin interferes with neurotransmitter function at nerve-muscle junction
Host responses influence outcomes
host response to microbe causes or augments damage at infection siteHepatitis BImmune response kills infected liver cells
microbe causes immunosuppression, increasing susceptibility to other agentsMeasles virus, HIVExacerbation of tuberculosis; opportunistic infections
Effects depend on maturational status of host organ systems at time of infection
microbe may be teratogenic depending on gestational periodRubella virusFirst trimester congenital infection results in a spectrum of birth defects
MECHANISMS OF MICROBIAL PATHOGENESISPart II
Effects depend on complex pathogen:host interactionsInterference with differentiated cell functionLymphocytic choriomeningitis viruspersistent viral infection alters neurotransmitter or hormone production without killing cells (dementia, diabetes, hypothyroidism)
Molecular mimicryStreptococcusantibodies to bacteria also bind to host, causing cardiac or CNS damage (autoimmunity)
Longterm effects of infection?Multiple sclerosislatitude where one lives before puberty determines risk for a disease that begins in early adulthood
Psychiatric disordersGestational exposure increases risk for schizophrenia, a disorder that first manifests in adolescence or early adulthood
MECHANISMS OF MICROBIAL PATHOGENESISPart III
Emerging Microbial Concepts:Infectious Causes of Chronic Disease
Web-based Analysis of GreeneChip DataAccounts: Australian Biosecurity CRC (Boyle); CDC (Nichol & Towner); Stanford
(Hirschberg & Davis); Institut Pasteur Shanghai (Deubel); Univ of Colorado(Holmes & Dominguez); Wadsworth Center,NYSDOH (St. George & Dean)
Enteroviruses in Feces of Healthy Norwegian Children Aged 3-28 Months (145 of 1,255 samples)
2.43HEVUntyped
1.62CAV19HEV-C
1.62HEV-BaHEV-B
0.81EV30HEV-B
0.81EV25HEV-B
8.911EV18HEV-B
1.62EV13HEV-B
0.81EV11HEV-B
2.43EV9HEV-B
0.81EV5HEV-B
1.62EV3HEV-B
3.24CBV5HEV-B
2.43CBV4HEV-B
7.39CBV3HEV-B
4.05CBV1HEV-B
3.24CAV9HEV-B
3.24HEV-AaHEV-A
14.518HEV71HEV-A
0.81CAV16HEV-A
4.86CAV14HEV-A
5.67CAV10HEV-A
10.513CAV6HEV-A
5.67CAV5HEV-A
8.911CAV4HEV-A
2.43CAV2HEV-A
Percent (n=124)EpisodesSerotypeSpecies
5’ UTR mutationsmay inhibit EVfitness
A STAGED STRATEGY FOR PATHOGEN DETECTION
Hi Throughput Sequencing
Disclosure454 Life Sciences Scientific Advisory Board 2003-present
Novel high throughput pyrosequencing slide-based platformAlgorithm for Reductive Analysis of Sequence DataProgram for automated identification of pathogen sequences
Outbreak of Transplant-Associated Encephalitis Identification of a novel arenavirus
Colony Collapse Disorder Profile of an emerging threat to agriculture and economic welfare
Primer
Repeat
Trimming FilteringClustering Assembly
Raw Reads
host
ContigsTrimmed Reads Unique Reads Non-host ReadsReductive Analysis of Highthroughput Sequencing Data
Contigs and SingletsContigs and Singlets
Candidates withNucleotide Homology
Candidates withNucleotide Homology
BLASTN
Candidates withProtein HomologyCandidates with
Protein Homology
BLASTX
viruses
bacteria
fungi
metazoans
parasites
Sequence ð TaxonomySequence ð Taxonomy
Candidate organism
High Throughput Sequencing in Pathogen Surveillance and Discovery
Encephalitis MassTag PCR
140,000 sequences obtained
14 (0.01%) Old World Arenavirus sequences
S-segmentGreeneChipVr1.5 array
High throughput sequencing of pooledrandom PCR products
2007: 3 cases of transplant associated disease Organ Donor: 57 y/o M (thalamic bleed)
Recipients: 63 y/o F (kidney), 44 y/o F (kidney), 64 y/o F (liver)
• S-segment, 12 sequences• L-segment, 2 sequences
Identical sequence in donor and recipients
50,000 RNA copies in liver and kidney<100 RNA copies in brain and serum
To Bee or Not to Bee…Colony Collapse Disorder
Global pollination of > 90 fruit and vegetable crops$14.6B/year in US alone
Pepper Persimmon (native)Plums and PrunePumpkinsRadishRapeRaspberryRutabagaSafflower SquashStrawberrySunflowerSweetcloverTangeloTangerineTendergreensTrefoilTurnipsVetchWatermelonsYucca
viruses
bacteria
fungi
metazoans
parasites
Varroa destructor mite
Kynetoplastide parasite species
Nosema sp.
Neisseria species
Gamma proteobacteria
Viruses
ssRNA (+)
Dicistroviridae
Cripavirus
Black Queen Virus
Israel acute paralysis virus
Kashmir bee virus
Iflavirus
Sacbrood virus
Deformed wing virus
Chronic bee paralysis virus
Large unselected cohort (100,000)
Prospective collections of clinical data and biologic specimens begins early in gestationBiological and clinical phenotypes Longitudinal trajectory of diseaseFunctional genomics, proteomics, toxicology, as well as genetics
Microbial pathogenesis is complex• Susceptibility is a function of genes, age, other factors• Mechanisms can be direct, indirect• Expression of disease may be delayed
The microbiome is largely uncharted.
The advent of new tools for microbial surveillance canchange the landscape of chronic as well as acute diseases.
Realization of the promise of these tools will require aninvestment not dissimilar to that allocated for genetics.
In the period that Einstein was active as a professor one of his students came to him and said: “The questions of this year’s exams are the same as last year!”
“True, “ Einstein said, “but this year all the answersare different.”