1 / 44

TB Pathogenesis

TB Pathogenesis. Stacey Rizza, M.D. Disclosures. None. Objectives. Explain how M. tuberculosis is transmitted Describe the immune response to M. tuberculosis Understand the targets of immunotherapies for M. tuberculosis.

neorah
Download Presentation

TB Pathogenesis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. TB Pathogenesis Stacey Rizza, M.D.

  2. Disclosures • None

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

  4. 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

  5. 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

  6. 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

  7. Mycobacterium tuberculosis Recovery, an Samurai Showdown

  8. 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.

  9. 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

  10. TB Pathogenesis

  11. 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

  12. TB PathogenesisWhat it does CDC.gov-Transmission and Pathogenesis of Tuberculosis

  13. 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

  14. TB PathogenesisWhat it does Tubercle bacilli multiply in alveoli, where infection begins CDC.gov-Transmission and Pathogenesis of Tuberculosis

  15. TB PathogenesisWhat it does A small number of tubercle bacilli enter bloodstream and spread throughout body CDC.gov-Transmission and Pathogenesis of Tuberculosis

  16. 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

  17. TB PathogenesisWhat it does shell breaks down and tubercle bacilli escape and multiply • If the immune system CANNOT keep tubercle bacilli under control, bacilli begin to multiply rapidly and causeTB disease • This process can occur in different places in the body CDC.gov-Transmission and Pathogenesis of Tuberculosis

  18. Clinical Disease M. tuberculosis can cause

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. The Great Tuberculosis Paradox

  26. 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

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. Adaptive Immunity to M. tuberculosis Activates and recruits Immune cells Kills mycobacteria-infected cells Resp2010.15:433

  34. 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

  35. 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

  36. Histology of TB diseaseCollateral damage Atlas of Pathology, 2nd edition, Romana

  37. 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

  38. 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?

  39. 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

  40. 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

  41. 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

  42. Vaccine Candidates for MTB Phase I and phase IIa trials

  43. 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?

  44. TB Pathogenesis Immunopathogenesis! La Miseriaby Cristobal Rojas (1886). World Health Organization

More Related