M. tuberculosis causes tuberculosis, a classic mycobacterial dis-ease in humans. The capability of M. tuberculosis for intracellu-lar growth in alveolar macrophages is the main determinant of virulence of the bacteria.
The factors determining the virulence of M. tuberculosis are poorly understood. M. tuberculosis does not produce any toxin. Although cord factor and sulfolipids are toxic substances pro-duced by mycobacterium, their existence as virulence factors is doubtful.
Cord factor: Cord factor was so called because of the falsebelief that it is responsible for producing serpentine cords typically found on the surface of liquid or on solid media by M. tuberculosis. The cord factor was originally thought to be avirulent factor, which no longer holds true.
Sulfolipids: Sulfolipids are of doubtful virulence factor. Theirexact role in pathogenesis of the disease is not known. They are found to be associated with virulence of tubercle bacilli by preventing fusion of phagosome and lysosome inside the mac-rophages, thereby allowing the bacteria to multiply within the macrophages. The main pathology in the infected tissue caused by mycobacterial infection is primarily due to responses of the host to M. tuberculosis infection rather than any virulence factor produced by it.
Tuberculosis may be primary or postprimary depending on the time of infection and the type of host immune response.
Primary tuberculosis: Primary tuberculosis represents the ini-tial infection caused by M. tuberculosis in an infected host. This condition is usually seen in young children in endemic countries like India. On inhalation of the aerosolized bacteria, the bacilli reach the lower respiratory tract. Majority of the inhaled bacteria are killed by the natural defensive mechanisms of the upper respi-ratory tract. The bacilli that survive these defensive mechanisms reach the lungs and enter alveolar macrophages. The phagocy-tosed bacilli inhibit acidification of the phagosomes and prevent subsequent fusion of phagosome and lysosome. This makes the bacteria multiply freely either in the phagosome or in the cyto-plasm. Multiplication inside the cells leads to destruction of the cells and release of mycobacteria. This is followed by further cycles of phagocytosis of bacteria by macrophages, multiplica-tion of mycobacteria, and lysis of macrophages.
Some bacilli are transported by macrophages to the hilar lymph nodes. They are attracted to this site by the presence of bacilli, cellular components, and chemotactic factors, such as complement C5a of the serum. This leads to formation of the focus known asGhon’s focus, which is formed of multinucleated giant cells known as Langerhans cells. The focus is commonly found in the lower lobe or in the lower part of the upper lobe of the lungs. This focus is also associated with enlargement of the hilar lymph nodes. Both Ghon focus and enlarged lymph nodes constitute the primary complex, which usually develops in 3–8 weeks after infection by tubercle bacilli. This primary com-plex is associated with the development of tuberculin hypersensi-tivity. The lesion in majority of cases heals spontaneously within 2–6 months.
If small numbers of bacilli are present, the bacilli are destroyed by macrophages with minimal tissue damage. However, if many bacilli are present, it leads to development of tissue necrosis. Multiple host factors contribute to the process of tissue necrosis.
These include (a) local activation of the complement,
(b) exposure to macrophage-derived hydrolytic enzymes,
(c) cytokine toxicity, and (d) reactive oxygen intermediates.
The bacilli may be present as dormant in this stage or may become reactivated in old age, or following therapy, or follow-ing immunosuppressive disease. Reactivation of the site causes postprimary (secondary) tuberculosis.
Postprimary (secondary) tuberculosis: Postprimary tuber-culosis is caused either by reactivation of latent infection or by exogenous reinfection. Reactivation of primary lesion occurs more commonly in patients with decreased immunity, such as patients receiving transplants, those infected with human immunodeficiency virus (HIV), and in the elderly patients. The secondary tuberculosis differs from primary tuberculosis in the following features:
1. Granulomas of secondary tuberculosis occur more com-monly in the upper lobes of the lung. The lesions in the lungs undergo caseous necrosis and tissue destruction, resulting in the formation of the cavities in the immuno-deficient hosts. The lesions disseminate widely into lungs and other organs, such as kidneys, bones, meninges, etc.
2. Involvement of lymph nodes is usual.
3. The cavities may rupture into blood vessels, causing dis-semination of mycobacteria in the body or these may rup-ture into airways, releasing mycobacterium in aerosol and sputum.
Tubercle: Tubercle is the key pathology in tuberculosis.This is an avascular granulomatous condition. It is com-posed of a peripheral zone of lymphocytes and fibroblasts and a central zone consisting of giant cells with or without caseation. The lesions are mainly of two types: (a) exudative and (b) productive tubercular lesions.
Exudative tuberculous lesion is an acute inflammatory reac-tion. This condition is associated with an increase in the number of polymorphonuclear leukocytes and subsequently with that of lymphocytes and mononuclear cells as well as accumulation of fluid. This lesion is seen more commonly in patients (i) infected with more virulent bacilli, (ii) with an increased load of bacilli, and (iii) with increased delayed type hypersensitivity (DTH) host response.
Productive tuberculosis lesion is primarily cellular. It is associ-ated with protective immunity rather than DTH response.
M. tuberculosis infection in an infected host induces CMI.The CMI is manifested either as delayed tuberculin hyper-sensitivity or as resistance to infection. The course of infec-tion is determined by the interaction of hypersensitivity or immunity.
Tuberculin hypersensitivity reaction: This was firstdescribed by Robert Koch in experimentally infected animals, such as guinea pigs. Demonstration of this tuberculin reactivity in guinea pigs is known as Koch’s phenomenon. Koch phenome-non is demonstrated by subcutaneous injection of pure culture of virulent tubercle bacilli in a normal guinea pig. Initially, no immediate visible reaction is observed at the site of inoculation in the guinea pigs. But after 10–14 days, a hard nodule appears at the site of inoculation, which soon breaks down to from an ulcer that persists till the animal dies of progressive tubercu-losis. The regional lymph nodes draining the region become enlarged and caseous.
In contrast, when a guinea pig already inoculated 4–6 weeks earlier by tubercle bacilli is injected with tubercle bacilli, an individual lesion develops at the site of second inoculation within 24–48 hours. The lesion undergoes necrosis in another day to produce a shallow ulcer that heals rapidly, involving the regional lymph nodes and other tissues.
The DTH can be induced by live attenuated and killed bacilli, bacillary products, and tubercular protein. Usually live or killed bacilli or tubercular protein (tuberculin) are employed for demonstration of hypersensitivity reaction. This hypersen-sitivity reaction can be transferred passively by cells, but not by serum.
Tuberculin test: Tuberculin test is performed to demonstratedelayed type IV or cell-mediated hypersensitivity reaction to tubercle bacilli. Originally, the tuberculin test was performed by using a protein known as old tuberculin (OT) prepared by Robert Koch.
The OT is a protein component of tubercle bacilli prepared from a 6–8 week culture filtrate of M. tuberculosis cultured in 5% glycerol, which is concentrated 10-fold by evaporation on a steam bath. The OT is a crude protein, which consists of pro-tein as a constituent but varies from batch to batch in its purity and potency. This has now been replaced by the use of PPD of tubercle bacilli.
Humoral immunity: Humoral immunity is characterizedby the development of antibodies in serum, but they do not play any role in conferring immunity against the bacteria. Antibodies against polysaccharide, proteins, and phosphate antigens of tubercle bacilli have been demonstrated in serum of patients with tuberculosis. These serum antibodies, however, are not protective.