Mycobacterium Tuberculosis
Molecular overview of Host immune responses and evasion strategies of bacterium
Presented by
Zainab Zaffar
Microbiology M.Phil. Sem. Fall
Outlines
Ø Introduction
Ø Virulence factors of Mycobacterium
Ø Pathogenesis of Tuberculosis
Ø Adhesion and evasion of immune response
Ø Conclusion
Introduction
• Mycobacterium tuberculosis is one of the most effective
human pathogens, with one-third of the world’s population
(about 2 billion people) being infected.
• It is an acid-fast, rod-shaped bacillus with mycolic acid
cell wall.
• Tb is communicable disease and patients with pulmonary
tb are most important source of infection.
• Infection is initiated by inhalation of droplet nuclei.
• Mycobacterium exhibits multidrug resistance, posing
significant challenges for treatment.
Virulence factors of
Mycobacterium
• Phosphatidyl-myo-inositol
mannosides (PIMs)
• Lipomannan (LM)
• Lipoarabinomannan (LAM)
• ESAT-6 (EsxA or Rv3875)
Diagram adapted from Ramon-Luing et.al (2023)
Pathogenesis Of Tuberculosis
Diagram adapted from Maison, D. P. (2022)
Adhesion and
evasion
• Mycobacteria utilize surface
molecules like adhesins and
glycolipids for attachment.
• These molecules interact with
specific receptors on host
cells.
• Adhesins contain conserved
domains enabling binding to
extracellular matrix proteins
like fibronectin, laminin, and
collagen.
Diagram adapted from Kumar et al., 2013)
Phagosome Maturation Process:
• Phagocytosis of M. tuberculosis by macrophages leads to phagosome
formation.
• Phagosome matures through fusion and fission events with endocytic
vesicles, forming the phagolysosome.
• Phagosome maturation is dependent on a Ca2+ signaling cascade, leading
to phosphorylation of phosphatidyl inositol to PI-3P.
• Acidification by vH+-ATPase are crucial for phagolysosome formation.
Inhibition of Phagolysosome Maturation by M. tuberculosis
• Exclusion of vH+-ATPase and modulation of Ca2+ signaling cascade (e.g., SapM-mediated hydrolysis of PI-
3P) inhibit acidification and phagosome-lysosome fusion.
• Retention of the host protein TACO (coronin-1) on M. tuberculosis phagosomes inhibits phagosome-
lysosome fusion.
The innate immune response
Host Innate immune Response Evasion of innate immune response
• M. tuberculosis is phagocytosed by antigen-presenting • The 19 kDa lipoprotein of M. tuberculosis is a TLR2
cells in the lung, including alveolar macrophages and agonist that inhibits MHC-II expression and antigen
dendritic cells. processing by macrophages, leading to insufficient
activation of effector T cells.
• M. tuberculosis components are recognized by host
pattern recognition receptors (PRRs) such as Toll-like • Mannose-capped lipoarabinomannan (ManLAM) in the
receptors (TLRs). M. tuberculosis cell envelope interacts with mannose
receptors on macrophages, inhibiting IL-12 production
• Signaling through TLRs leads to production of pro-
and phagolysosome maturation, promoting M.
inflammatory cytokines like TNF-α, IL-1, IL-12, and
tuberculosis survival.
nitric oxide.
Granuloma formation
Diagram adapted from Luke, Erica & Swafford (2022)
Dampening of macrophage functions
• T cell-derived cytokines, mainly IFN-γ and TNF-α, activate macrophages to
generate nitric oxide and other RNI through iNOS.
• Inhibition of iNOS activity or disruption of the iNOS gene abolishes the
protective effect of RNI and leads to reactivation of latent infection.
• The M. tuberculosis gene ahpC detoxifies peroxynitrite, a reactive compound
formed by the reaction of nitric oxide with superoxide.
• Haemoglobin-like proteins encoded by glbN and glbO in M. tuberculosis help
blunt the toxic effects of RNI.
Role of IFN-γ
• IFN-γ is the key cytokine for protective immune response against M. tuberculosis
• IFN-γ is produced mainly by CD4+ T cells, CD8+ T cells, and NK cells
• IFN-γ synergizes with TNF-α to activate macrophages and kill intracellular bacilli by
production of nitric oxide
• IFN-γ augments antigen presentation, leading to recruitment and activation of CD4+ and
CD8+ T cells
• However, M. tuberculosis 19-kDa lipoprotein can attenuate the macrophage response to
IFN-γ by blocking transcription of a subset of IFN-γ-responsive genes
Role of Apoptosis in Host Defense
• Apoptotic vesicles containing mycobacterial antigens are taken up by dendritic cells,
leading to CD8+ T cell activation and IFN-γ production.
• IFN-γ produced by CD8+ T cells activates uninfected macrophages to produce reactive
nitrogen intermediates (RNI) for efficient killing of intracellular M. tuberculosis.
• Components such as cell wall components, ManLAM, the secA2-encoded virulence-
related secretion system, superoxide dismutase (encoded by sodA), and NADH
dehydrogenase (encoded by nuoG) are involved in inhibiting macrophage apoptosis.
Role of the ESX-1 Secretion
System
• The RD1 region encodes proteins that form a
novel protein secretion system called ESX-1
(type VII secretion system).
• ESX-1 is involved in the export of key M.
tuberculosis proteins, including ESAT-6 and
CFP-10, which lack signal sequences for export.
• ESAT-6 can dissociate from its partner CFP-10
at lower pH and disrupt artificial membranes,
causing cytolysis.
Diagram Adapted from Augenstreich, J., & Briken, V. (2020).
Conclusion
• The molecular analysis of host immune responses to Mycobacterium tuberculosis
reveals a complex interaction between the bacterium and host defense
mechanisms.
• Understanding these interactions can lead to the development of novel therapeutic
interventions and vaccines.
• Future research should focus on molecular interactions using advanced
technologies and interdisciplinary collaborations to combat tuberculosis globally.
References
• Ramon-Luing, Lucero & Palacios, Yadira & Ruiz, Andy & Téllez Navarrete, Norma & Chávez-Galán, Leslie. (2023). Virulence
Factors of Mycobacterium tuberculosis as Modulators of Cell Death Mechanisms. Pathogens. 12. 839. 10.3390/pathogens12060839.
• Luke, Erica & Swafford, Kimberly & Shirazi, Gabriella & Venketaraman, Vishwanath. (2022). TB and COVID-19: An Exploration
of the Characteristics and Resulting Complications of Co-infection. Frontiers in Bioscience-Scholar. 14. 6. 10.31083/j.fbs1401006.
• Maison, D. P. (2022). Tuberculosis pathophysiology and anti-VEGF intervention. Journal of Clinical Tuberculosis and Other
Mycobacterial Diseases, 27, 100300.
• Augenstreich, J., & Briken, V. (2020). Host cell targets of released lipid and secreted protein effectors of mycobacterium
tuberculosis. Frontiers in cellular and infection microbiology, 10, 595029.
• Ahmad, S. (2011). Pathogenesis, immunology, and diagnosis of latent Mycobacterium tuberculosis infection. Journal of
Immunology Research, 2011.
• Kaufmann, S. H. (2001). How can immunology contribute to the control of tuberculosis?. Nature Reviews Immunology, 1(1), 20-30.
