An overall scheme of pathogenesis by M. tuberculosis is shown in Figure 1. It describes primary tuberculosis, which typically results in a Ghon focus in the lower lung. Primary tuberculosis can heal by fibrosis, can lead to progressive lung disease, can cause bacteremia and miliary tuberculosis, or can cause hematogenous dissemination resulting in no immediate disease but with the risk of reactivation in later life.
Fig1. Pathogenesis by Mycobacterium tuberculosis. CNS = central nervous system; GI = gastrointestinal; HIV = human immunodeficiency virus. (Reproduced with permission from Le T, Bhushan V, Sochat M: First Aid for the USMLE Step 1, 25th ed. New York, NY: McGraw Hill; 2015.)
If the primary infection heals without causing disease, it is called a latent infection. Of those exposed to M. tuberculosis, approximately 90% develop latent infection and approximately 10% develop disease. Of those who have latent infection, approximately 10% progress to active disease (reactivation) at a later time, whereas 90% remain latent.
Figure 1 also describes secondary tuberculosis with a cavity in the upper lobes. This can cause disease directly or result in reactivation disease in later life with central nervous system lesions, vertebral osteomyelitis (Pott’s disease), or involvement of other organs.
M. tuberculosis produces no well-recognized exotoxins and does not contain endotoxin in its cell wall. However, M. tuberculosis produces two proteins that appear to play a role in pathogenesis. One is tuberculosis necrotizing toxin (TNT), which cleaves nicotinamide adenine dinucleotide (NAD) within macrophages resulting in death of the infected macrophage. The other is early secreted antigen-6 (ESAT-6), a protein that reduces the innate immune response by reducing gamma interferon production, thereby enhancing the virulence of the organ ism. The precise role of these proteins in pathogenesis remains to be determined.
The organism preferentially infects macrophages and other reticuloendothelial cells. M. tuberculosis survives and multiplies within a cellular vacuole called a phagosome. The organism produces a protein called exported repetitive protein that pre vents the phagosome from fusing with the lysosome, thereby allowing the organism to escape the degradative enzymes in the lysosome.
Lesions are dependent on the presence of the organism and the host response. There are two types of lesions:
(1) Exudative lesions, which consist of an acute inflammatory response and occur chiefly in the lungs at the initial site of infection.
(2) Granulomatous lesions, which consist of a central area of giant cells containing tubercle bacilli surrounded by a zone of epithelioid cells. These giant cells, called Langhans’ giant cells, are an important pathologic finding in tuberculous lesions. A tubercle is a granuloma surrounded by fibrous tissue that has undergone central caseation necrosis. Tubercles heal by fibro sis and calcification.
The primary lesion of tuberculosis usually occurs in the lungs. The parenchymal exudative lesion and the draining lymph nodes together are called a Ghon complex. Primary lesions usually occur in the lower lobes because airflow to those areas is greatest. In contrast, reactivation lesions usually occur in the apices because oxygenation is greatest there and lymph flow is low allowing the organism to remain at the site. Reactivation lesions also occur in other well-oxygenated sites such as the kidneys, brain, and bone. Reactivation is seen primarily in immunocompromised or debilitated patients.
Spread of the organism within the body occurs by two mechanisms:
(1) A tubercle can erode into a bronchus, empty its caseous contents, and thereby spread the organism to other parts of the lungs, to the gastrointestinal tract if swallowed, and to other persons if expectorated.
(2) It can disseminate via the bloodstream to many internal organs. Dissemination can occur at an early stage if cell-mediated immunity fails to contain the initial infection or at a late stage if a person becomes immunocompromised.
