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

1
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 (lt50
  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
Immunology of M. tuberculosis infection and
disease (slide 2)

• TLRs
• Chemokines
• Cytokines
• Antigens
• T cell subsets
• Effector mech.
• Immune evasion

INFECTION
REACTIVATION
Bacterial Load
Failure (Immunopathogenesis?)
Innate
Adaptive
5
Known knowns, known unknowns, unknown unknowns
and dogma for immunology of human TB (slide 3,
adapted from Donald Rumsfeld 03)

• 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)
• CD8s critical, cause of BCG failure
• It is all about cytokines (cytokine interventions
  have failed)
• Now its Tregs, Th17
• Unknown unknowns
• TLRs in last century
• Why all T cell vaccines have failed so far (TB,
  HIV)?

6
(No Transcript)
7
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

8
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

9
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)

10
Protective Adaptive Immunity to M. tuberculosis
Macrophages and T cells
IL-12, IFN-g, TNF-a
cytokines
IL-2
T cell
M?
Growth inhibition
CTL
(FasL/CD95L, granzymes, perforin, granulysin)

• IL-12, TNF-alpha, IFN-gamma
• IL-2 for T cell expansion
• Cytotoxic Effector T Cells (CTL)
• Growth inhibition of M. tuberculosis