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Chapter 2 : Stages in the Pathogenesis of Human and Rabbit Tuberculosis

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Abstract:

After the inhalation of tubercle bacilli by rabbits and humans, the disease tuberculosis may progress through the following stages. In humans, the disease begins with the establishment of only a single primary pulmonary tubercle. Stage 1: Ingestion and often destruction of bacilli by pulmonary alveolar macrophages. Stage 2: Logarithmic growth of bacilli within nonactivated macrophages that entered the developing tubercle from the bloodstream. Stage 3: Arrest of the logarithmic bacillary growth by delayed-type hypersensitivity, which kills the bacilli-laden macrophages and often forms a solid caseous center in the tubercle. Stage 4a: In hosts with weakly developed cell-mediated immunity, enlargement of the tubercle and its caseous center with hematogenous dissemination of the bacilli. Stage 4b: In hosts with strongly developed cell-mediated immunity, stabilization or regression of the tubercle. Stage 5: Liquefaction of the caseous center, extracellular bacillary growth, cavity formation, and bronchial dissemination of the bacilli. These stages are not distinct but blend into each other. Also, stages 3, 4, and 5 may occur in the same lung and even in different parts of the same lesion, depending on the local concentration of bacilli and their tuberculin-like products. Native and acquired resistance is never absolute, because a large number of tubercle bacilli (which have grown extracellularly in a cavity) can overwhelm even the best-developed host resistance and cause secondary pulmonary lesions.

Citation: Dannenberg, Jr. A. 2006. Stages in the Pathogenesis of Human and Rabbit Tuberculosis, p 22-33. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch2
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Figures

Image of FIGURE 1
FIGURE 1

Stage 1. An alveolar macrophage that has ingested and killed the two tubercle bacilli in a phagocytic vacuole. The cytoplasm of this macrophage is darkly shaded to depict a high degree of activation, i.e., high levels of lysosomal and oxidative enzymes. Most alveolar macrophages are nonspecifically activated by the variety of inhaled particles that they ingest. In humans, an alveolar macrophage is usually able to kill an inhaled tubercle bacillus, except when the bacillus is unusually virulent or the macrophage is poorly activated. Reproduced with permission from reference 4.

Citation: Dannenberg, Jr. A. 2006. Stages in the Pathogenesis of Human and Rabbit Tuberculosis, p 22-33. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch2
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Image of FIGURE 2
FIGURE 2

Changes in the number of virulent human-type tubercle bacilli (H37Rv) in the lungs of Lurie’s natively resistant and natively susceptible rabbits at different intervals after an aerosol infection. By 7 days, the resistant rabbits had inhibited the growth of the bacilli 20 to 30 times more effectively than did the susceptible rabbits, but, from then on, the two curves were parallel. At 4 to 5 weeks, the susceptible rabbits had about 13 times more primary pulmonary tubercles in their lungs than did the resistant rabbits. The means and their standard errors are shown. Reproduced with permission from reference 8.

The number of tubercle bacilli in the lungs of the resistant rabbits failed to decrease during the period illustrated, because liquefaction with extracellular multiplication of the bacillus readily occurred in these rabbits (7, 8). Liquefaction did not occur in the susceptible rabbits (7, 8), because their macrophages probably developed only low levels of hydrolytic enzymes.

Inhaled virulent bovine-type tubercle bacilli (Ravenel S) grew to greater titers than did H37Rv, but produced similar curves (28) (shown in chapter 15).

Citation: Dannenberg, Jr. A. 2006. Stages in the Pathogenesis of Human and Rabbit Tuberculosis, p 22-33. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch2
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Image of FIGURE 3
FIGURE 3

Stage 2. An early primary pulmonary tubercle, in which tubercle bacilli have multiplied logarithmically within macrophages that have immigrated into the lesion from the bloodstream. These newly arrived macrophages are nonactivated and incompetent. Their cytoplasm is unshaded to depict the lack of activation. In fact, the phagocytic vacuoles in the cytoplasm of these nonactivated macrophages seem to provide an ideal environment for mycobacterial multiplication. Stage 2 is called the stage of symbiosis, because the bacilli are multiplying, the macrophages are accumulating, and neither the host nor the parasite is injured by the other. Reproduced with permission from reference 4.

Citation: Dannenberg, Jr. A. 2006. Stages in the Pathogenesis of Human and Rabbit Tuberculosis, p 22-33. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch2
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Image of FIGURE 4
FIGURE 4

An early pulmonary tuberculous lesion with a caseous center surrounded by blood-borne macrophages. The alveolar macrophages (recognized by their dark staining for the lysosomal enzyme β-galactosidase) have accumulated peripherally in nearby alveoli. More details on this lesion are given in Fig. 5 of chapter 9. Magnification, ×330. Reproduced with permission from reference 4.

Citation: Dannenberg, Jr. A. 2006. Stages in the Pathogenesis of Human and Rabbit Tuberculosis, p 22-33. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch2
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Image of FIGURE 5
FIGURE 5

A 2-week pulmonary lesion produced in a rabbit by the inhalation of virulent human-type tubercle bacilli (H37Rv) (8). The lesion consists of blood-borne nonactivated macrophages in which large numbers of bacilli had multiplied intracellularly. Note that, in this stage of symbiosis (i.e., before DTH develops), even numerous intracellular bacilli do not injure the macrophages. In other words, the bacillus is rather innocuous before DTH develops, and it is the host’s own DTH reaction that kills tissues during this disease. Stained with carbol-fuchsin, counterstained with methylene blue. Magnification, ×730. Reproduced with permission from reference 8.

Citation: Dannenberg, Jr. A. 2006. Stages in the Pathogenesis of Human and Rabbit Tuberculosis, p 22-33. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch2
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Image of FIGURE 6
FIGURE 6

Stage 3. A tubercle 3 weeks of age with a caseous necrotic center and a peripheral accumulation of partly activated macrophages (lightly shaded) and lymphocytes (small dark cells). The first stages of caseation occur when the tissue-damaging DTH response to a high concentration of tuberculin-like products kills the nonactivated macrophages that have allowed the bacilli to multiply logarithmically within them. The dead and dying macrophages are depicted by fragmented cell membranes. Intact and fragmented bacilli are present, both within macrophages and within the caseum. Tubercle bacilli do not multiply in solid caseum. Reproduced with permission from reference 4.

Citation: Dannenberg, Jr. A. 2006. Stages in the Pathogenesis of Human and Rabbit Tuberculosis, p 22-33. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch2
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Image of FIGURE 7
FIGURE 7

(A) Stage 4a. An established tubercle 4 to 5 weeks of age similar to those found in Lurie’s susceptible rabbits. It has an enlarging caseous center. The bacilli escaping from the edge of this center are ingested by poorly activated incompetent macrophages. In such macrophages, the bacilli again find a favorable intracellular environment in which to multiply. They do so until the tissue-damaging DTH (to high concentrations of tuberculin-like products) again kills these new bacilli-laden macrophages and enlarges the caseous necrotic center. This sequence may be repeated multiple times. Lung tissue is destroyed, and the bacilli are spread by the lymphatic and hematogenous routes to other sites. Metastatic lesions develop in which the tissue destruction continues. This pattern of tuberculosis is seen in immunosuppressed individuals, such as HIV/AIDS patients. In this cartoon, several partly activated macrophages are lightly shaded to indicate that such susceptible hosts develop only relatively weak CMI. Reproduced with permission from reference 4. (B) Stage 4b. An established tubercle 4 or 5 weeks of age similar to those found in Lurie’s resistant rabbits. The caseous center remains small, because the bacilli escaping from its edge are ingested by the highly activated (competent) macrophages (darkly shaded) that surround the caseum. In these activated macrophages, the bacilli cannot multiply and are eventually destroyed. Such effective macrophages were activated by T cells and their cytokines. If the caseous center remains solid and does not liquefy, the disease will be arrested by this CMI response. This scenario occurs in healthy immunocompetent humans who show positive tuberculin reactions and yet no clinical and often no X-ray evidence of the disease. Reproduced with permission from reference 4.

Citation: Dannenberg, Jr. A. 2006. Stages in the Pathogenesis of Human and Rabbit Tuberculosis, p 22-33. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch2
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Image of FIGURE 8
FIGURE 8

Photograph of stage 4a: a caseous tubercle in the lungs of one of Lurie’s susceptible rabbits 5 weeks after the inhalation of human-type tubercle bacilli. Bacilli escaping from the caseous center (lower left) are ingested by the surrounding poorly activated macrophages, i.e., incompetent immature epithelioid cells (upper right), where they again find a favorable intracellular environment in which to grow (Fig. 7A). Magnification, ×550. Reproduced with permission from reference 39.

Citation: Dannenberg, Jr. A. 2006. Stages in the Pathogenesis of Human and Rabbit Tuberculosis, p 22-33. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch2
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Image of FIGURE 9
FIGURE 9

Stage 5. A recently formed cavity discharging liquefied caseous material into a bronchus. In liquefied caseum, the bacilli may multiply extracellularly, reaching large numbers. High concentrations of tuberculin-like products are produced and local tissues are destroyed, including the wall of an adjacent bronchus (illustrated here). The liquefied caseous material is then discharged into the airways, and the bacilli disseminate to other parts of the lung and to the environment. Reproduced with permission from reference 4.

The large quantities of bacilli and their antigens in liquefied caseum may overwhelm a formerly effective CMI, causing progression of the disease in Lurie’s resistant rabbits, as well as in immunocompetent humans. Also, among such large numbers of bacilli, mutations causing antimicrobial resistance may occur. Lurie’s susceptible rabbits do not liquefy caseum or form cavities.

Citation: Dannenberg, Jr. A. 2006. Stages in the Pathogenesis of Human and Rabbit Tuberculosis, p 22-33. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch2
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Image of FIGURE 10
FIGURE 10

Wall of a cavity from one of Lurie’s genetically resistant rabbits 8 weeks after the inhalation of human-type bacilli (H37Rv). The liquefied caseous tissue (right) and liquefying caseous tissue (left) contain a large number of (rod-shaped) acid-fast bacilli. Such bacilli were formerly inhibited in solid caseous tissue, but they grew profusely in the liquefied caseum in the wall of this cavity. Stained with carbol-fuchsin, counterstained with methylene blue. Magnification, ×540. Reproduced with permission from reference 8.

Citation: Dannenberg, Jr. A. 2006. Stages in the Pathogenesis of Human and Rabbit Tuberculosis, p 22-33. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch2
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References

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Tables

Generic image for table
TABLE 1

Five stages of tuberculosis

Citation: Dannenberg, Jr. A. 2006. Stages in the Pathogenesis of Human and Rabbit Tuberculosis, p 22-33. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch2

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