Last Updated on January 15, 2020 by Sagar Aryal
Virulence factors of Mycobacterium tuberculosis
A. Mycolic acid and Lipoarabinomannan (LAM)
- Waxy layer that protects the bacteria from many host factors and also to many antibiotics including beta lactamases.
- Muramyl dipeptide (from peptidoglycan) complexed with mycolic acids can cause granuloma formation, phospholipids induce caseous necrosis.
- LAM is structurally and functionally related to the O antigenic lipopolysaccharides of other bacteria.
- Biological activities of LAM include strong seroreactivity, inhibition of interferon gamma mediated activation of macrophages, induction of cytokine production and release by macrophages, scavenging reactive oxygen intermediates, and suppression of T-cell proliferation.
- LAM has been identified as a key ligand of dendritic cell (DC)-specific intracellular adhesion molecule-3 grabbing nonintegrin (SIGN).
B. ESX 1 secretion system
- Helps in secretion of many proteins and enzymes that help the organism to survive in the phagosome.
- Mediates the delivery of bacterial products into the macrophage cytoplasm.
- Prevents the fusion of lysosome to phagosome and hence protects bacteria from phagolysosomal activity.
C. Phagosome maturation factors
- Ure that inhibits the acidification of early phagosome.
- Superoxide dismutase (SOD) that detoxifies host reactive oxygen substances (ROS).
- The nlA gene product which might inhibit host defenses by interfering with host cell apoptosis.
Pathogenesis of Mycobacterium tuberculosis
1. Portal of entry
- The infectious bacilli gains its entry to human host from inhalation as droplets from atmosphere.
- The first line of defense of host tries to ward off the bacteria by tracheal and bronchial epithelium.
- When bacteria survive from first line of defense, they enter the lungs.
2. Primary tuberculosis
- The bacteria are phagocytosed by alveolar macrophages in lung, entraps the bacteria in phagosome and action of lysosome along with phagosome collectively called as phagolysosome to kill the bacteria.
- When the bacteria survive the initial host defense mechanism, it attacks alveolar macrophages ad gain access to lung parenchyma, survives in phagosome and induce a localized cell mediated proinflammatory response leading to granuloma formation.
- The granuloma protects the bacteria and generally appear after 3 weeks of primary infection.
- When fully developed, this lesion, a chronic granuloma, consists of three zones: (1) a central area of large, multinucleated giant cells containing tubercle bacilli; (2) a mid zone of pale epithelioid cells, often arranged radially; and (3) a peripheral zone of fibroblasts, lymphocytes, and monocytes.
- The centre of the granuloma contains a mixture of necrotic tissue and dead macrophages.
- Being metabolically very active, the macrophages in the granuloma consume oxygen, and the resulting anoxia and acidosis in the centre of the lesion probably kills most of the bacilli.
- Granuloma formation is usually sufficient to limit the primary infection.
- The lesions become quiescent and surrounding fibroblasts produce dense scar tissue, which may become calcified called ghon focus .
- Programmed cell death (apoptosis) of bacteria-laden macrophages by cytotoxic T cells and natural killer (NK) cells contributes to protective immunity by generating a metabolic burst that kills tubercle bacilli.
3. Latent tuberculosis
- In most infected individuals, the primary infection resolves but some residual tubercle bacilli enter a poorly understood stage of latency or dormancy.
- This is mostly observed in immunocompromised cases eg. HIV or aging.
4. Post primary tuberculosis
- Reactivation of dormant foci of tubercle bacilli or exogenous reinfection leads to post-primary tuberculosis, which differs in several respects from primary disease.
- For unknown reasons, reactivation or reinfection tuberculosis tends to develop in the upper lobes of the lungs.
- Proteases liberated by activated macrophages soften and liquefy the caseous material, and an excess of tumour necrosis factor and other immunological mediators causes the wasting and fevers characteristic of the disease.
- The interior of the tuberculoma is acidic and anoxic, and contains few viable tubercle bacilli.
- Eventually, the expanding lesion erodes through the wall of a bronchus, the liquefied contents are discharged and a well aerated cavity is formed.
- The atmosphere of the lung, with a high carbon dioxide level, is ideal for supporting the growth of the bacilli, and huge numbers of these are found in the cavity walls.
- Once the cavity is formed, large numbers of bacilli gain access to the sputum, and the patient becomes an open or infectious case.
- In post-primary tuberculosis, dissemination of bacilli to lymph nodes and other organs is unusual.
- Instead, spread of infection occurs through the bronchial tree so that secondary lesions develop in the lower lobes of the lung and, occasionally, in the trachea, larynx and mouth.
- Bacilli in swallowed sputum cause intestinal lesions.
- Secondary lesions may also develop in the bladder and epididymis in cases of renal tuberculosis.
- Post-primary cutaneous tuberculosis (lupus vulgaris) usually affects the face and neck.
Clinical manifestation of tuberculosis
1. Primary or pulmonary tuberculosis
- Primary tuberculosis typically is considered a disease of the respiratory tract.
- Common presenting symptoms include:
- low-grade fever
- night sweats
- anorexia(loss of appetite)
- weight loss.
- A patient who presents with pulmonary tuberculosis usually has a productive cough, along with low-grade fever, chills, myalgias (aches), and sweating; however, these signs and symptoms are similar for influenza, acute bronchitis, and pneumonia.
2. Disseminated tuberculosis
- Organs besides the lungs can become involved after infection with M. tuberculosis complex organisms.
- These organs include the following:
- Genitourinary tract
- Lymph nodes (cervical lymphadenitis)
- Central nervous system (meningitis)
- Bone and joint (arthritis and osteomyelitis)
- Pleural lining (pleuritis)