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

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”)

7. Panel III: Immune Relevancy Sacred “cows”, questions and other musings

8. Questions to consider….. • Can host responses/markers tell us when infection progresses to disease? • Or is it detecting something from MTB that tells us CFUs are increasing? • Is Th1 vs. Th2 paradigm (still) useful? • Ineffectual/failed Th1 rather than Th2? • Balance of cytokines or do antigens matter? • For vaccines likely? For progression maybe not? For relapse/reinfection don’t know? • Evidence that host responses are responsible for pathology? • Aren’t granulomas in the right places good? Does it depend on the stage of infection? Can we intervene to prove it? • What’s up with the lungs? • Why the sluggish response? What is unique about the lungs as immune environment/sanctuary for MTB?

9. How can natural/experimental infection in animals help with these questions? • Natural history of infection and progression to disease (many) • Transition between stages/markers of transition • Pathology-granuloma, caseation, cavitation (rabbit, guinea pig) • MTB mutants/host genetic variants that differ in induction of pathology with similar CFU • Role of innate vs. adaptive immunity (mouse, primate, bovine) • Models difficult to infect, innate KO’s • Genetics of different stages (mouse, bovine, fish, ?others) • Infection, progression, reactivation vs. relapse • Drug Treatment (mouse, rabbit, primate, fish) • Latent vs. active infection (penetration/efficacy, PK, ARV) • Vaccine (mouse, guinea pig, primate, bovine) • Infection, dissemination vs. re-activation • Co-pathogenesis-HIV or helminth co-infection (primate) • Maybe asking too much…….