Mechanism of Pathogenesis of Mycobacterium tuberculosis
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a highly infectious disease that primarily affects the lungs. Mtb is a highly successful pathogen, and its ability to cause disease lies in its complex and intricate pathogenesis mechanisms.
1. Entry and Initial Infection
- Inhalation of infectious droplets: Mtb enters the body primarily through inhalation of aerosolized droplets containing the bacteria, expelled from an infected individual during coughing, sneezing, or speaking.
- Attachment to alveolar macrophages: Upon entering the lungs, Mtb attaches to alveolar macrophages, the primary immune cells in the alveoli. This attachment is mediated by interactions between specific receptors on the macrophage surface and molecules present on the Mtb cell wall.
- Phagocytosis and survival within macrophages: Mtb is then engulfed by macrophages through phagocytosis. However, Mtb has evolved sophisticated mechanisms to survive within macrophages, a crucial step in its pathogenesis.
2. Survival and Replication within Macrophages
- Inhibition of phagosome-lysosome fusion: Mtb prevents the fusion of the phagosome (the vesicle containing the bacteria) with the lysosome, an organelle that contains digestive enzymes. This prevents the destruction of the bacteria by the lysosomal enzymes.
- Secretion of virulence factors: Mtb secretes various virulence factors that interfere with macrophage functions. These factors include:
- ESAT-6 and CFP-10: These proteins inhibit phagosome maturation and disrupt macrophage function.
- Lipomannan (LM): LM interferes with phagosome-lysosome fusion and triggers macrophage apoptosis, a form of programmed cell death.
- Mycobacterial surface antigens: These antigens interfere with macrophage signaling and immune responses.
3. Immune Evasion and Spread
- Latency: Mtb can evade the host immune system by entering a latent stage, where it remains dormant within macrophages and does not actively replicate.
- Spread within the body: If the immune system is unable to contain the infection, Mtb can spread from the lungs to other organs through the lymphatic system and bloodstream.
- Granuloma formation: The host immune response to Mtb leads to the formation of granulomas, which are walled-off areas of infected tissue. Granulomas attempt to contain the infection but can also act as reservoirs for persistent infection.
4. Disease Progression
- Primary TB: This is the initial infection, usually manifested by localized inflammation and granulomas in the lungs.
- Latent TB: The infected individual remains asymptomatic with Mtb in a dormant state.
- Active TB: If the immune system weakens, the infection can reactivate and progress to active TB, characterized by symptoms like coughing, fever, weight loss, and night sweats.
- Extrapulmonary TB: Mtb can spread to other organs, leading to extrapulmonary TB, affecting tissues such as the brain, kidneys, bones, and lymph nodes.
5. Drug Resistance
- Genetic mutations: Mtb can develop resistance to anti-TB drugs due to genetic mutations that alter the target site of the drug or enhance the expression of drug efflux pumps.
- Multidrug-resistant TB (MDR-TB): Mtb resistant to at least two of the most important anti-TB drugs (isoniazid and rifampicin).
- Extensively drug-resistant TB (XDR-TB): Mtb resistant to isoniazid and rifampicin, plus at least one fluoroquinolone and one injectable drug.
Conclusion
Mtb pathogenesis is a complex interplay between the bacterium's virulence factors and the host immune response. Understanding these mechanisms is crucial for developing effective diagnostic tools, preventive measures, and treatment strategies to combat the global TB epidemic.
