tb

• Mycobacterium tuberculosis (Mtb)


  A highly successful intracellular pathogen that has evolved sophisticated mechanisms to evade and modulate the host immune response, enabling it to establish persistent infection and cause disease
• Interplay between Mtb and the host immune system

  1. Involves a complex interplay of molecular and cellular interactions

  2. Bacteria employ various strategies to counteract the host's defense mechanisms
• Mycobacterium tuberculosis Evasion Mechanisms

  • Cell Wall Composition
  • Mycolic Acids
  • Lipoarabinomannan (LAM)
  • Phenolic Glycolipids (PGLs)
  • Inhibition of Phagosome Maturation
  • Secreted Effector Proteins
  • Modulation of Host Immune Signaling
  • Escape from Phagosome
• Cell Wall Composition


  • The unique cell wall structure of Mtb plays a crucial role in its ability to evade and resist host immune defenses
  • The cell wall is composed of several layers, including an outer membrane, a mycolyl-arabinogalactan-peptidoglycan complex, and an inner plasma membrane
• Mycolic Acids


  • Long-chain α-alkyl, β-hydroxy fatty acids that form the inner leaflet of the outer membrane
  • They contribute to the low permeability and hydrophobicity of the cell wall, rendering Mtb resistant to many antibiotics and host-derived antimicrobial compounds
• Lipoarabinomannan (LAM)


  • A major lipoglycan found in the cell wall of Mtb
  • It inhibits phagosome-lysosome fusion, suppresses the oxidative burst in macrophages, and induces the production of anti-inflammatory cytokines, aiding in immune evasion
• Phenolic Glycolipids (PGLs)


  • Present in the outer membrane of Mtb
  • They contribute to the inhibition of phagosome maturation and the suppression of various host immune responses, such as antigen presentation and T cell activation
• Inhibition of Phagosome Maturation


  Upon entry into host macrophages, Mtb employs several strategies to prevent phagosome maturation and acidification, creating a favorable environment for its survival and replication
• Secreted Effector Proteins


  • Mtb secretes virulence factors, such as ESAT-6 and CFP-10, through the ESX-1 secretion system
  • These proteins disrupt the recruitment of host factors required for phagosome maturation, preventing the fusion of phagosomes with lysosomes
• SapM


  A secreted phosphatase that dephosphorylates host proteins involved in phagosome maturation, thereby blocking the recruitment of the vacuolar ATPase responsible for acidification
• LipY


  A lipase that hydrolyzes host-derived lipids, disrupting the membrane trafficking events required for phagosome maturation
• Modulation of Host Immune Signaling

  Mtb employs various strategies to modulate host immune signaling pathways, suppressing inflammatory responses and evading detection by the immune system
• Inhibition of NF-κB and MAPK Pathways

  Mtb interferes with the NF-κB and MAPK signaling pathways, which are crucial for the production of pro-inflammatory cytokines and the activation of the innate immune response
• Suppression of Cytokine Production

  Mtb inhibits the production of key pro-inflammatory cytokines, such as TNF-α, IL-12, and IFN-γ, which are essential for effective immune responses against the bacteria
• Interference with Antigen Presentation

  Mtb downregulates the expression of MHC class II molecules on infected macrophages, impairing the presentation of Mtb antigens to CD4+ T cells and hampering the adaptive immune response
• Escape from Phagosome


  In some cases, Mtb can escape from the phagosome into the cytosol of the host cell, enabling it to evade lysosomal degradation and potentially access new nutrient sources
• ESX-1 Secretion System


  The ESX-1 secretion system is responsible for the translocation of virulence factors, such as ESAT-6 and CFP-10, across the phagosomal membrane, facilitating the escape of Mtb into the cytosol
• Cytosolic Survival


  Once in the cytosol, Mtb employs strategies to counteract host cytosolic defenses, such as the production of neutralizing enzymes and the modulation of host cell signaling pathways
• Host Immune Response to Mycobacterium tuberculosis

  • Innate Immune Response
  • Adaptive Immune Response
• Innate Immune Response


  • Phagocytic Cells
  • Natural Killer (NK) Cells
  • Complement System
• Phagocytic Cells


  Macrophages and neutrophils are the primary phagocytic cells that recognize and engulf Mtb through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs)
• Phagocytosis


  Upon recognition of Mtb, macrophages and neutrophils engulf the bacteria through phagocytosis, initiating a series of antimicrobial mechanisms within the phagosome
• Phagosome Maturation


  The phagosome containing Mtb undergoes a series of maturation steps, including fusion with lysosomes, acidification, and the production of reactive oxygen and nitrogen species (ROS and RNS), aimed at killing the internalized bacteria
• Cytokine Production


  Activated phagocytes produce pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, which enhance the antimicrobial responses and recruit additional immune cells to the site of infection
• Natural Killer (NK) Cells


  • NK cells are important in the early innate immune response against Mtb
  • They can directly recognize and kill infected cells through the release of cytotoxic granules or the induction of apoptosis
  • Additionally, NK cells produce cytokines, such as IFN-γ, that enhance the antimicrobial activities of macrophages
• Complement System


  • The complement system plays a role in the opsonization of Mtb, facilitating its recognition and phagocytosis by macrophages and neutrophils
  • Complement proteins can also directly lyse Mtb or recruit other immune cells to the site of infection
• Adaptive Immune Response


  • T Cell Responses
  • B Cell Responses
  • Granuloma Formation
  • Cytokine Networks
• T Cell Responses


  • CD4+ T Helper Cells
  • CD8+ Cytotoxic T Cells
  • T Cell Memory
• CD4+ T Helper Cells

  • CD4+ T helper cells, particularly the Th1 subset, are essential for the activation and recruitment of macrophages to the site of infection
  • They produce cytokines, such as IFN-γ and TNF-α, which enhance the antimicrobial activities of macrophages and promote the formation of granulomas
• CD8+ Cytotoxic T Cells

  CD8+ cytotoxic T cells recognize Mtb-derived peptides presented on MHC class I molecules and can directly kill infected cells through the release of cytotoxic granules or the induction of apoptosis
• T Cell Memory


  • The development of immunological memory is crucial for long-term protection against Mtb reinfection
  • Memory T cells can rapidly respond to subsequent encounters with Mtb, enhancing the immune response and limiting disease progression
• B Cell Responses


  • Antibody Production
  • Antigen Presentation
• Antibody Production

  Antibodies produced by B cells can opsonize Mtb, facilitating phagocytosis by macrophages and neutrophils
• Antigen Presentation


  B cells can act as professional antigen-presenting cells, presenting Mtb-derived peptides to T cells and contributing to the activation of the adaptive immune response
• Granuloma Formation


  1. The formation of granulomas is a hallmark of the immune response against Mtb

  2. Granulomas are organized structures composed of macrophages, multinucleated giant cells, and lymphocytes, aiming to contain and limit the spread of Mtb
• Containment of Mtb


  Granulomas provide a physical barrier that restricts the dissemination of Mtb and prevents the spread of the infection to other tissues
• Immune Cell Recruitment


  Granulomas serve as a site for the recruitment and accumulation of immune cells, including macrophages, T cells, and B cells, facilitating the coordination of the immune response against Mtb
• Hypoxic Conditions


  The hypoxic and nutrient-deprived conditions within granulomas can induce a dormant state in Mtb, contributing to the establishment of latent infection
• Cytokine Networks


  • IFN-γ
  • TNF-α
  • IL-12 and IL-23
  • IL-10 and TGF-β
• IFN-γ

  • Produced primarily by Th1 cells and NK cells, IFN-γ is a central cytokine in the immune response against Mtb
  • It enhances the antimicrobial activities of macrophages, promotes antigen presentation, and induces the production of other pro-inflammatory cytokines