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TB Pathogenesis. Stacey Rizza, M.D. Objectives. Explain how M. tuberculosis is transmitted Describe the immune response to M. tuberculosis Understand the targets of immunotherapies for M. tuberculosis.

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tb pathogenesis

TB Pathogenesis

Stacey Rizza, M.D.

objectives
Objectives
  • Explain how M. tuberculosis is transmitted
  • Describe the immune response toM. tuberculosis
  • Understand the targets of immunotherapies for M. tuberculosis
slide3

Whatever happened to the good old days: you know, dirty attics, tuberculosis and general all-round suffering? (Sir Arnold Wesker)How Old is M. tuberculosis?

  • 150 years
  • 325 years
  • 550 years
  • 1000 years
  • 4000 years
tb pathogenesis what is it
TB PathogenesisWhat is it?
  • One of the oldest recorded human afflictions
  • Bone TB from individuals who died 4,000 years ago
  • Assyrian clay tablets record hemoptysis 7th century BC
  • Hippocrates describes symptoms of consumption from the 5th century BC

Clin. Microbiol. Rev. July 2003 vol. 16 no. 3 463-496

tb pathogenesis what is it1
TB PathogenesisWhat is it?
  • Until mid-1800s, many believed TB was hereditary or a working man’s disease
  • 1865 Jean Antoine-Villemin proved TB was contagious
  • 1882 Robert Koch discovered M. tuberculosis, the bacterium that causes TB

Mycobacterium tuberculosis

Image credit: Janice Haney Carr

CDC.gov- Transmission and Pathogenesis of Tuberculosis

mycobacterium tuberculosis
Mycobacterium tuberculosis

Recovery, an

Samurai Showdown

mycobacterium tuberculosis what is it
Mycobacterium tuberculosisWhat is it?
  • Caused by the Mycobacterium M. tuberculosis
  • Small, aerobic, non-motile bacillus
  • High lipid content- lipid bilayer
    • Does not stain well
    • Can live in a dry environment for weeks
    • Can withstand some disinfectants
  • Divides at the slow rate of 16-20 hours.
mycobacterium tuberculosis what is it1
Mycobacterium tuberculosisWhat is it?
  • Can be identified under a regular light microscope.
  • Most mycobacterium retain stains even after washes and therefore are called “acid-fast” bacilli or AFB
  • Common staining techniques are:
    • Ziehl-Neelsen stain-bright red
    • Auramine-rhodamine stain-fluorescence microscopy
mycobacterium tuberculosis what it does
Mycobacterium tuberculosis What it does
  • TB is spread person to person through the air via droplet nuclei
  • M. tuberculosis may be expelled when an infectious person:
    • Coughs
    • Sneezes
    • Speaks
    • Sings
  • Transmission occurs when another person inhales droplet nuclei

CDC.gov-Transmission and Pathogenesis of Tuberculosis

tb pathogenesis what it does
TB PathogenesisWhat it does

Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to the small alveoli

CDC.gov-Transmission and Pathogenesis of Tuberculosis

tb pathogenesis what it does1
TB PathogenesisWhat it does

Tubercle bacilli multiply in alveoli, where

infection begins

CDC.gov-Transmission and Pathogenesis of Tuberculosis

tb pathogenesis what it does2
TB PathogenesisWhat it does

immune cells

form a barrier

  • Within 2 to 8 weeks, MTB can be phagocytosed by alveolar immune cells
  • The phagocytosed immune cells transport the MTB to local lymph nodes for T cells priming and cloning
  • The immune cells form a barrier shell that keeps the bacilli contained and under control (LTBI)

CDC.gov-Transmission and Pathogenesis of Tuberculosis

who does the heavy lifting
Who Does the Heavy Lifting?

What cells phagocytose the MTB bacilli once they reach the alveoli?

  • CD4 T cells
  • B cells
  • Macrophages
  • Defensin cells
  • NK cells
events following entry of bacilli tb pathogenesis
Events following entry of bacilliTB Pathogenesis

Stage1:

  • Phagocytosis of MTB by Alveolar macrophage
  • Destruction of MTB, but some evade destruction & continue to multiply and then infect bystander macrophages

Dr. h. c. Stefan H.E. Kaufmann

Max-Planck-Gesellschaft

events following entry of bacilli tb pathogenesis1
Events following entry of bacilliTB Pathogenesis

Stage 2:

  • Influx of Polymononuclear cells (PMN) and Monocytes-differentiate into Macrophage
  • In some cases, it fails to eliminate the bacilli completely
  • Logarithmic growth of bacilli-little tissue destruction

The PMNs come marching in

events following entry of bacilli tb pathogenesis2
Events following entry of bacilliTB Pathogenesis

Stage 3:

  • Antigen specific T-cells are recruited to the site and activate monocytoid cells and differentiate into two types of Giant cells
    • Epithiliod
    • Langhan
  • Infection is walled off from rest of the body which prevents dissemination of bacilli.

Pharm & Therap 113;2007: 264

events following entry of bacilli tb pathogenesis3
Events following entry of bacilliTB Pathogenesis

Stage 4:

  • Stage of Latency (Granuloma) disrupts under conditions of failing immune surveillance & leads to endogenous reactivation of dormant bacilli
  • Characterised by caseation necrosis

Front. Immunol., 07 January 2013

the great tuberculosis paradox
The Great Tuberculosis Paradox
  • Up to 50% of people with close and repeated contact with confirmed index cases, even in high burden areas, have no immunodiagnostic evidence of Tb disease.
  • Sterilizing innate immunity
  • Likely related to host factors
what f actor does not impact the likelihood of m tuberculosis transmission
What factor does NOT impact the likelihood of M. tuberculosis transmission?
  • Intensity of exposure
  • Exposure duration
  • The gender of the infected individual
  • Recipient host factors
  • M. tuberculosis strain virulence
tb immunopathogenesis
TB Immunopathogenesis
  • Immune system vs. MTB
    • Local inflammation
    • Activation of a/b T cells
    • Enhanced cytokine response
    • A lot of IFN-g released
  • MTB immune evasion techniques
    • Suppressive cytokines (TGFb)
    • Effector molecules
    • Treg cells

Resp 2010. 15:433

tb immunopathogenesis the achilles heel
TB ImmunopathogenesisThe Achilles heel
  • Increased susceptibility to TB with:
    • Suppressed CD4 or CD8 T cell levels- HIV
    • TNFa blockage
    • Hereditary IFN-g
    • IL-2 receptor abnormalities or inhibition
  • Insight into immune requirements for protection against MTB
slide24

Innate Immunity to M. tuberculosis

Toll-like receptor

Activate NK, T cells, macrophages

NF-kB and cytokines

Vit D Receptor

Phagocytic killing of pathogens

Resp 2010.15:433

innate immunity to m tuberculosis
Innate Immunity to M. tuberculosis
  • Promote bacterial killing with phagosomal maturation, producing reactive nitrogen and oxygen intermediates
  • Several pathways and cell types mediate an innate immune response to MTB
  • Therefore, many individuals may fail to have an immunodiagnostic evidence of MTB infection despite prolonged or high-risk exposure
adaptive immunity to m tuberculosis
Adaptive Immunity to M. tuberculosis
  • Mycobacterial infected macrophages and dendritic cells present antigens to T cells and B cells.
  • Macrophage apoptosis releases apoptotic vesicles with MTB to uninfected DC for even greater antigen presentation.

Pasteur institute

adaptive immunity cd4 t cell
Adaptive ImmunityCD4 T cell
  • Th1
    • INFg, TNFa, IL2, GM-CSF
    • Stimulation of CTL, macrophage activation
  • Th2
    • IL4, IL5, IL10, IL13
    • B cell stimulation
    • Suppress Th1
  • Th17
    • IL17, IL17F, IL21, Il22
    • Defesin, recruit neutrophils and monocytes
  • T reg
    • TGFb
    • Modulate T cell response
adaptive immunity to m tuberculosis1
Adaptive Immunity to M. tuberculosis

Activates and recruits

Immune cells

Kills mycobacteria-infected cells

Resp2010.15:433

adaptive immunity to m tuberculosis2
Adaptive Immunity to M. tuberculosis
  • B cells were not thought to have a significant role in protecting against MTB
  • Recent work showed that B cells were needed in MTB infected mice by acting as an intermediary for cellular immunity and the complementpathway.

Eur J. Immunolo 2009;39:676

adaptive immunity to m tuberculosis3
Adaptive Immunity to M. tuberculosis
  • Memory T cells are created specific to MTB antigens.
  • Memory T cells are active and proliferate with recall responses
  • Specific, practical, clinical biomarkers of protective immunity has not been established

Nat Med 2005;11:S33

histology of tb disease collateral damage
Histology of TB diseaseCollateral damage

Atlas of Pathology, 2nd edition, Romana

histology of tb disease
Histology of TB disease

Ziehl-Neelsen stain

  • Delayed hypersensitivity reaction
  • Central Caeseating necrosis
  • Surrounded by lymphocytes, multi-nucleate giant cells and epitheloid macrophages
  • Organisms may be identified within the macrophages

H&E stain

National University of Singapore, Dept. of Pathology

immunomodulation for cure of tb
Immunomodulation for Cure of TB
  • Improve sterilizing immunity
  • Decrease collateral damage of the immune system
  • 95% of bacterial sterilization occurs in 2 weeks, but 6 months of therapy is needed.
    • Is immune modulation needed to stop a destructive immune pattern to a protective one?
immunomodulation for cure of tb1
Immunomodulation for Cure of TB
  • Drive a Th1 response, turn off T reg
    • IL2, INFg, steroids, thalidomide, TNFa antagonist-failed!
  • IVIG dramatically improves mycobacterial sterilization in a mouse model
  • Many other agents in different stages of discovery and clinical trials

Infect Immun 2005.73:6101

m tuberculosis vaccines
M. Tuberculosis vaccines
  • MTB antigens ESAT-6, CFP-10 Ag85
    • Found in latently infected, or exposure individuals
    • Induce cytokine specific immune response
    • Provide protective immunity in animal models
  • Provide a protective antigen through a vaccine or viral vector/gene therapy
m tuberculosis vaccines bacille calmette guerin
M. Tuberculosis vaccinesBacilleCalmette Guerin
  • BCG protective effect
    • Age, background infection rates, virulence of MTB strain, co-infection with helminths, T cell immunity to helminths, malnution
    • All factors that module the immune system
  • Protects against MTB dissemination
  • May protect against adult MTB infection in household contacts
  • Prevent primary infection and/or prevent transition from LTBI to infection
vaccine candidates for mtb
Vaccine Candidates for MTB

Phase I and phase IIa trials

challenges in vaccine development
Challenges in vaccine development
  • Children and adolescence
  • HIV/TB co-infection – poor T cell response
  • HIV/Helminth co-infection- strong Th2 response
  • No good functional immune assays to predict a sterilizing response
  • ? Role of Aerosolized vaccination?
tb pathogenesis2
TB Pathogenesis

Immunopathogenesis!

La Miseriaby Cristobal Rojas (1886).

World Health Organization

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