How the host sees and responds to pathogens

Transcription

1 How the host sees and responds to pathogens David A. Relman, Stanford University IOM Forum on Microbial Threats March 17, 2005

2 Issues Pathogens and commensals: conserved patterns and pathways Sources of variation in host response? Future experimental paths

3 Pathogens and commensals: conserved patterns and pathways From the perspective of the host, are commensals and pathogens created equal?

4 I&P- or bacteria-specific (e.g., ornithine decarboxylase 1; ADA, CPM) Common induction Donor-specific (interferon signaling: OAS, MX1, etc) Common repression

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7 stress (ROI, UV) infection (LPS, viruses...) IL-1, TNF-α NFAT IκB kinase* NFκB kinase* Fos/Jun (AP-1) cytokines/gf IL-1β TNF-α IL-6 G-CSF GM-CSF SCF chemokines MIP-1α MIP-1β MIP-2α IL-8 RANTES transcript. regulators c-rel REL-B NFκB1 NFκB2 IκB-α other ICAM-1 vimentin IL-2R c-iap2 BFL-1

8 30,000 foot view of diverse infectious diseases Marburg Ebola Anthrax Smallpox Monkeypox (>265 specimens, 11 million data points) MHC class II Ribosomal proteins Immunoglobulin Proliferation Interferon NFkB

9 Pathogens and commensals: conserved patterns and pathways Perhaps the issue with respect to response programs and disease is simply when, where, how much, and not what.

10 Pathogens and commensals: conserved patterns and pathways Archaea lack the classical patterns. Can they cause disease?

11 Bacteria The Tree of Life (based on rrna sequences) Archaea Eukarya from: Pace NR. A molecular view of microbial diversity and the biosphere. Science 1997; 276:734

12 Why are there no known archaeal pathogens? Opportunity? Capability? Microbial virulence vs. host response Detection

13 26-MB 24-MB 22-MB

14 Relative abundance of archaeal small subunit rdna 25 Mean % Archaea sites/58 subjects 18/50 subjects with periodontitis harbor archaea (77% periodontal sites) 5 0 Severe Moderate Slight Gingivitis Healthy Tongue Subgingival Site Periodontal Status Lepp PW, et al. Proc Natl Acad Sci USA 2004;101:

15 Model of oral anaerobic community interactions methanogens -Methanobrevibacter oralis 4H 2 +CO 2 CH 4 +2H 2 O ( G = -131 KJ mol -1 ) - OOCCH2CH2COO - ( G = -86 KJ mol -1 ) - OOCCHCHCOO - + H 2 fumarate reducers -Campylobacter rectus -Selemonas spp. -Actinobacillus spp. primary fermenters syntrophic partner/ secondary fermenter 4H 2 +CO 2 sulfate-reducers SO 2-4 CH 3 COO - + 3H + -Desulfovibrio spp. H 2 S 2CO 2 + 2H 2 O ( G = KJ mol -1 ) CH 3 COO - + H + + 2H 2 O ( G = -95 KJ mol -1 ) homoacetogens -treponemes? -Methane, SRB and acetate values from Gibson et al 1993.

16 Community as pathogen that is, disease due to a community disturbance pathogenic states

17 Issues Pathogens and commensals: conserved patterns and pathways Sources of variation in host response? Future experimental paths

18 Sources of variation in host response? host genetics microbial stimulus time, dose specimen

19 Correlates with peripheral blood expression patterns from 77 healthy persons: sources of variability Whitney A et al, PNAS 2003; 100:

20 Donor-intrinsic gene expression males 48 PBMC samples from 19 individuals clustered on the basis of genes with highest intrinsic scores (340) females Whitney A et al, PNAS 2003; 100:

21 Sources of variation in host response? host genetics other signatures of human individuality? microbial stimulus time, dose specimen

22 Gut ecosystem: lumenal, adherent, host?

23 Microbial diversity in colon: study design 3 healthy patients (IBD study controls) endoscopic bx from 6 colonic mucosal sites/pt + fecal broad range rdna PCR analyzed seqs/mucosal sample, seqs/fecal sample; total: 11, ,524 archaeal