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Human M. tuberculosis infection/ disease: classical pathology and immunology (Slide -1)

NIAID-DMID: -AI70022. Human M. tuberculosis infection/ disease: classical pathology and immunology (Slide -1). W. Henry Boom, M.D. Tuberculosis Research Unit (TBRU) Case Western Reserve University. Cattle Prod 1950. Route(s) of Infection & Natural Course (Slide 0).

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Human M. tuberculosis infection/ disease: classical pathology and immunology (Slide -1)

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  1. NIAID-DMID: -AI70022 Human M. tuberculosis infection/ disease: classical pathology and immunology (Slide -1) W. Henry Boom, M.D. Tuberculosis Research Unit (TBRU) Case Western Reserve University Cattle Prod 1950

  2. Route(s) of Infection & Natural Course (Slide 0) • small vs. large droplet aerosol • repeated exposure • ?infectious dose (animals: 1-10 CFU) • ?repeated infection IO PROGRESSIVE: PEDS.+IMMUNOCOMP. (5%) REACTIVATION/ADULTS (5-10%) Bacterial Load INFECTION (90+%) Time (mos-yrs)

  3. Pulmonary Tuberculosis(slide 1) • Cough (+/-RBC), Wt. Loss, Night sweats • 109-1011 CFU • Diagnosis: Sputum Smear/Culture (<50% paucibacillary) • Pathology: Caseating Granulomas, Necrosis, Cavitation (?Host or Microbe) • Death: • Cachexia • Respiratory Failure • Dissemination (miliary, meningitis) • Massive Hemoptysis http://library.med.utah.edu/WebPath

  4. c l a s s I M H C c l a s s I I M H C C D 4 C D 8 T c e l l T c e l l - T C R a b M F - T C R a b Phos. Ag g - T C R d gd C D 1 r e s t r i c t e d T c e l l s D N T C R a b T c e l l CD25+ CD4 T cell Immunology of M. tuberculosis infection and disease (slide 2) INFECTION • TLR’s • Chemokines • Cytokines • Antigens • T cell subsets • Effector mech. • Immune evasion REACTIVATION Bacterial Load Failure (Immunopathogenesis?) Innate Adaptive

  5. Known: Adaptive immunity CD4+ T cell TNF-alpha IFN-gamma IL-12 Unknown: Genetics: which ones/stage (IFNgamma/IL12 pathway, NRAMP1, TNFalphaR, etc.) TLRs: which ones/when Chemokines: same (MCP1)? What does IFN-gamma do? Immunology of the lung: why so slow? Antigens matter: which ones, when, where? Dogma: “Immuno-pathogenesis” (HIV: cavitation related to CD4, but mortality still high) CD8’s critical, cause of BCG failure It is all about cytokines (cytokine interventions have failed) Now it’s Tregs, Th17……… Unknown unknowns: TLRs in last century Why all T cell vaccines have failed so far (TB, HIV)? TNF-a, IL-12 T M IFN-g “Known knowns, known unknowns, unknown unknowns” and dogma for immunology of human TB (slide 3, “adapted from Donald Rumsfeld ‘03”)

  6. TNF-a, IL-12 T M IFN-g, IL-10 Cytokines and M. tuberculosis • IFN-g • IFN-gR deficient humans • IFN-g KO mice • TNF-a • TNF-a and TNF-aR KO mice • anti-TNF-a antibodies in humans • IL-12 • IL-12R deficient humans • IL-12 KO mice • IL-10/TGF-b • Inhibit during active disease

  7. NIAID-DMID: -AI70022 Immune Evasion by M. tuberculosis • Innate: • Blocks Phagosomal Maturation • Limited fusion with lysosomes • Exclusion Na+ Dep. Proton ATP-ase • Retains Rab5 delays Rab7 acquisition • ? Sticking TACO-tryptophane aspartate-containing coat protein (murine) • Inhibition of Ca2+ rise prevents calmodulin/CaMKII recruitment of cathepsinD • Roles for LAM, PIM • Inactivates Bactericidal Mechanisms • oxygen radicals • nitric oxide • autophagy • Adaptive: • Inhibition of IFN-gamma regulated genes • Inhibition of MHC II Antigen Processing (lipoproteins/TLR-2) • Direct modulation of CD4+ T cell function • Inhibitory Cytokines (IL-10, TGF-beta) • T cell Apoptosis

  8. Models for what aspect of TB? • Pathology-granuloma, lung pathology, cavity, caseation (rabbit) • Immunology-innate vs. adaptive T cell immunity (mouse, primate,?bovine) • Genetics- risk for infection, progression, reactivation vs. relapse (?mouse, bovine) • Drug Treatment-latent vs. active infection (efficacy, PK, ARV interactions) (primate) • Vaccine- infection, dissemination vs. re-activation (mouse, guinea pig, primate) • Co-pathogenesis-HIV or helminth co-infection (primate)

  9. Protective Adaptive Immunity to M. tuberculosis: Macrophages and T cells IL-12, IFN-g, TNF-a cytokines • IL-12, TNF-alpha, IFN-gamma • IL-2 for T cell expansion • Cytotoxic Effector T Cells (CTL) • Growth inhibition of M. tuberculosis IL-2 T cell M Growth inhibition CTL (FasL/CD95L, granzymes, perforin, granulysin)

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