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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


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 Pathogenesis attics, tuberculosis and general all-round sufferingWhat 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 Pathogenesis attics, tuberculosis and general all-round sufferingWhat 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 attics, tuberculosis and general all-round suffering

Recovery, an

Samurai Showdown


Mycobacterium tuberculosis what is it
Mycobacterium tuberculosis attics, tuberculosis and general all-round sufferingWhat 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 tuberculosis attics, tuberculosis and general all-round sufferingWhat 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


Tb pathogenesis1
TB Pathogenesis attics, tuberculosis and general all-round suffering


Mycobacterium tuberculosis what it does
Mycobacterium tuberculosis attics, tuberculosis and general all-round sufferingWhat 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 Pathogenesis attics, tuberculosis and general all-round sufferingWhat 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 Pathogenesis attics, tuberculosis and general all-round sufferingWhat it does

Tubercle bacilli multiply in alveoli, where

infection begins

CDC.gov-Transmission and Pathogenesis of Tuberculosis


Tb pathogenesis what it does2
TB Pathogenesis attics, tuberculosis and general all-round sufferingWhat 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? attics, tuberculosis and general all-round suffering

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 attics, tuberculosis and general all-round sufferingfollowing 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 bacilli attics, tuberculosis and general all-round sufferingTB 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 bacilli attics, tuberculosis and general all-round sufferingTB 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 bacilli attics, tuberculosis and general all-round sufferingTB 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 attics, tuberculosis and general all-round suffering

  • 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


The great tuberculosis paradox1
The Great Tuberculosis Paradox attics, tuberculosis and general all-round suffering


What f actor does not impact the likelihood of m tuberculosis transmission
What attics, tuberculosis and general all-round sufferingfactor 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 attics, tuberculosis and general all-round suffering

  • 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 attics, tuberculosis and general all-round sufferingImmunopathogenesisThe 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


Innate Immunity to attics, tuberculosis and general all-round sufferingM. 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 attics, tuberculosis and general all-round sufferingM. 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 attics, tuberculosis and general all-round sufferingM. 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 Immunity attics, tuberculosis and general all-round sufferingCD4 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 attics, tuberculosis and general all-round sufferingM. tuberculosis

Activates and recruits

Immune cells

Kills mycobacteria-infected cells

Resp2010.15:433


Adaptive immunity to m tuberculosis2
Adaptive Immunity to attics, tuberculosis and general all-round sufferingM. 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 attics, tuberculosis and general all-round sufferingM. 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 disease attics, tuberculosis and general all-round sufferingCollateral damage

Atlas of Pathology, 2nd edition, Romana


Histology of tb disease
Histology of TB disease attics, tuberculosis and general all-round suffering

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 attics, tuberculosis and general all-round suffering

  • 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 attics, tuberculosis and general all-round suffering

  • 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 attics, tuberculosis and general all-round sufferingvaccines

  • 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 attics, tuberculosis and general all-round sufferingvaccinesBacilleCalmette 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 attics, tuberculosis and general all-round suffering

Phase I and phase IIa trials


Challenges in vaccine development
Challenges in vaccine development attics, tuberculosis and general all-round suffering

  • 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 attics, tuberculosis and general all-round suffering

Immunopathogenesis!

La Miseriaby Cristobal Rojas (1886).

World Health Organization


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