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Chapter 15 : Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs

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Abstract:

In recent times, mice have been by far the most frequently used animal for the study of tuberculosis. Guinea pigs and rabbits are used less often, and monkeys are used only occasionally. Rabbits die after an infection with virulent bovine-type tubercle bacilli, but eventually heal an infection with virulent human-type tubercle bacilli. Mice develop slowly progressing pulmonary tubercles with both bovine and human strains of tubercle bacilli, but the disease progresses more rapidly with the bovine strain. With virulent human-type bacilli, the tubercles of mice contain a larger number of viable bacilli than do the tubercles of rabbits and guinea pigs. Apparently, the low levels of delayed-type hypersensitivity (DTH) in mice and the rarity of caseous necrosis allow the bacillus to grow to higher titers in the logarithmic stage. After these titers are reached, the good cell-mediated immunity (CMI) developed by mice reduces the intracellular multiplication of the majority of the bacilli to almost a dormant state. However, because of the extensive lung destruction caused by tissue-damaging DTH, guinea pigs often die in less time than do rabbits and mice. Rhesus monkeys are very susceptible to tuberculosis, but cynomolgus monkeys are more resistant. Some cynomolgus monkeys can even stop the progression of the disease. Due to the differences in the pathogenesis of tuberculosis in rabbits, mice, and guinea pigs, all three species should be used for testing new vaccines prior to their trials in humans.

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
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Image of FIGURE 1
FIGURE 1

The number of viable human- and bovine-type tubercle bacilli in the lungs of natively resistant and susceptible rabbits at different intervals following quantitative airborne infection (6, 7, 75). This graph shows the increase in the number of viable bacilli relative to the initial number deposited into the pulmonary alveoli (see explanation below). All human-type tubercle bacilli are of reduced virulence for rabbits. The means are shown (see references 7 and 75 for the standard errors).

By 1 week after infection, the resistant rabbits had inhibited the growth of the human-type bacilli in their lungs about 25 times more effectively than did the susceptible rabbits, and the resistant rabbits had inhibited the growth of bovine-type bacilli about 5 times more effectively. From then on, the bacillary growth curves in both strains of rabbit were parallel. At 4 weeks, similar comparisons of the number of bacilli in the susceptible and resistant rabbits were about 20 times for the human type and about 2.5 times for the bovine type.

These findings indicate that bovine-type bacilli are harder to inhibit than human-type bacilli—both by native resistance (pulmonary alveolar macrophages) and by acquired resistance (T lymphocytes activating macrophages). These findings also indicate that both native and acquired resistance are much more effective in the genetically resistant group. Commercially available New Zealand White rabbits resemble Lurie’s resistant strain of rabbits (68, 69, 94–97).

The number of bacilli in the lungs of the resistant group failed to decrease during the period illustrated, because liquefaction with extracellular multiplication of the bacillus readily occurs in these rabbits (6). Liquefaction usually does not occur in the susceptible rabbits (6), because their macrophages probably develop only low levels of hydrolytic enzymes. Reproduced with permission from reference 75.

Note that this figure was derived from the results of many experiments, each using a somewhat different inhaled dosage. For this reason, the y axis represents the number of viable tubercle bacilli in the entire lung divided by one-third the number of bacilli inhaled. This ratio shows increases (or decreases) in the number of viable pulmonary bacilli at various times after infection. At 8 weeks, the lungs of the resistant and susceptible rabbits contained, respectively, an average of 2.2 × 108 and 3.4 × 108 viable bovine-type bacilli, and 2.2 × 106 and 25.5 × 106 human-type bacilli (see references 7 and 75).

The number of bacilli was estimated by culturing lung homogenates. The number of inhaled bacilli was calculated by sampling and culturing the aerosols with an impinger and determining the amount of air breathed by each rabbit calculated from its weight (6, 7, 75). Two-thirds of the small bacillary particles breathed by each rabbit impinge on the mucosa of the bronchial tree and are eventually swallowed. Only one-third reach the alveoli where the infection begins (6). In the graph, the number of tubercle bacilli inhaled into the alveoli is therefore one-third the number of bacilli that the rabbit breathed.

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
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Image of FIGURE 2
FIGURE 2

The number of viable virulent human-type (H37Rv) and bovine-type (Ravenel) tubercle bacilli in the lungs of C57BL/6 mice at different intervals following quantitative airborne infection (8). Note that the in vivo bacillary growth curves in mice resembled those found in rabbits (see Fig. 1), but in contrast to rabbits, H37Rv and Ravenel tubercle bacilli multiplied to the same levels in C57BL/6 mice (a relatively resistant strain). Reproduced with permission from reference 8.

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
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Image of FIGURE 3
FIGURE 3

The number of viable virulent human-type tubercle bacilli (H37Rv) in the lungs of BCG-vaccinated and control guinea pigs at different intervals following quantitative airborne infection (40). Note that the in vivo bacillary growth curves in guinea pigs resemble those found in rabbits (Fig. 1) and in mice (Fig. 2). Other experiments showed that the stationary phase in guinea pigs continues for at least 18 weeks (41). Note also that in the BCG-vaccinated guinea pigs, the logarithmic growth stage ends soon and that the number of viable tubercle bacilli in the stationary stage is markedly reduced (see text). The guinea pigs were immunized intradermally with live BCG 6 weeks before the aerosol challenge. Reproduced with permission from reference 40.

The number of tubercle bacilli in the stationary stage in guinea pigs is lower than the number found in mice (compare Fig. 2 and 3), because guinea pigs probably end the logarithmic stage sooner (although insufficient time points were plotted in these two figures to show this difference). Therefore, the good DTH of guinea pigs is probably more effective than the good CMI of mice in ending the logarithmic stage, which supports the principle that tissue-damaging DTH is an important host defense mechanism in controlling intracellular bacillary multiplication.

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
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Image of FIGURE 4
FIGURE 4

Viable counts and total counts of virulent tubercle bacilli (H37Rv) in the lungs of mice from 9 weeks to 25 weeks after an intravenous infection. After the lungs were homogenized, the viable counts were calculated from the CFU developing on plates containing solid culture medium. The total counts were calculated from the bacilli observed microscopically after acid-fast staining of spread smears made from the homogenates. During this time period, one of the four groups of mice received isoniazid-pyrazinamide (PZA/INH) daily to kill the bacilli.

Note that for untreated mice the average total counts were 0.3 to 0.4 logs higher (2.0 to 2.5 times) than the average viable counts, and that PZA/INH treatment markedly reduced the viable counts but had relatively little effect on the total counts. These findings indicate that (i) most of the dead tubercle bacilli persisted in mouse lungs for many weeks, (ii) most of the live bacilli in the untreated mice were in a dormant state, because if they had been multiplying and then had been killed, the total counts (including the dead bacilli) would have increased, and (iii) the good CMI developed by mice activated macrophages sufficiently to prevent the intracellular multiplication of most of the tubercle bacilli.

Note also that the 2.0- to 2.5-fold mean difference in total and viable counts suggests that at least some bacillary growth and destruction were occurring. In other words, at least some of the bacilli were not inhibited by the good CMI, which is probably the reason for the progression of the disease in mice until they succumb.

These results were confirmed in reference 2 using quantitative real-time PCR.

Reproduced with permission from reference 1. The same figure appears as Fig. 1 in chapter 6 of this volume.

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
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Image of FIGURE 5
FIGURE 5

A primary pulmonary tuberculous lesion in a C57BL/6 mouse 8 weeks after an aerosol inhalation of virulent human-type tubercle bacilli. On the right is the lesion’s center containing large viable epithelioid macrophages, some of which probably inhibited (or destroyed) the tubercle bacilli that they had ingested during the earlier stages of the infection. A few polymorphonuclear leukocytes have accumulated where some of these macrophages have disintegrated (far right). In the middle of the photograph is part of the mantle of compact lymphocytes, which surrounds the center of epithelioid macrophages. On the far left are a few foamy macrophages within the surrounding alveolar spaces. Many of these foamy macrophages are pulmonary alveolar macrophages that tend to accumulate around pulmonary tuberculous lesions (see Fig. 5 of chapter 9). Pulmonary alveolar macrophages often ingest surfactant, which gives them the foamy appearance. Stained with hematoxylin and eosin. Magnification, ×275. Photograph provided by P.-J. Cardona.

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
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Image of FIGURE 6
FIGURE 6

The outer layer of the 8-week lesion shown in Fig. 5. Note how these foamy cells fill the alveolar spaces. Tubercle bacilli (not shown) are occasionally present in some of these foamy macrophages. The bacilli were probably carried to the lesion’s periphery within macrophages that had migrated at an earlier time from the center. Such bacilli sometimes cause secondary lesions in nearby alveoli. Stained with hematoxylin and eosin. Magnification, ×275. Photograph provided by P.-J. Cardona.

In mice, few, if any, tubercle bacilli remain free in viable tissues or even in lymphatics, because bacilli released from disintegrating macrophages are soon ingested by other (still viable) macrophages. In animal species where cavities form, many free tubercle bacilli enter the airspaces, and some of these bacilli may be ingested by the alveolar macrophages. Mouse lesions do not liquefy and form cavities, so extracellular tubercle bacilli are rarely present.

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
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Image of FIGURE 7
FIGURE 7

A tuberculous lesion in a mouse similar to those shown in Fig. 5 and 6. Little or no necrosis occurs in mouse lesions, mainly because there is no thrombosis of the microvasculature. This photograph shows patent microvessels (white arrows) within the dense lymphocyte layer that surrounds the center, containing numerous viable epithelioid macrophages. The microvessels are easily identified by the intact erythrocytes that they contain. Stained with hematoxylin and eosin. Magnification, ×295. Photograph provided by P.-J. Cardona.

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
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Image of FIGURE 8
FIGURE 8

A guinea pig tuberculous lesion 4 weeks after an aerosol infection with virulent human-type tubercle bacilli. Note (from left to right) the pronounced caseous center, the typical tuberculous granulation tissue with many lymphocytes, and the nearby alveoli with slightly thickened walls. Stained with hematoxylin and eosin. Magnification, ×80. Photograph provided by P.-J. Cardona.

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
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Image of FIGURE 9
FIGURE 9

Another guinea pig tuberculous lesion 4 weeks after an aerosol infection with virulent human-type tubercle bacilli. Note (from left to right) the pronounced caseous center, the typical tuberculous granulation tissue, the surrounding fibroblasts, and the intact pleura. Stained with hematoxylin and eosin. Magnification, ×80. Photograph provided by P.-J. Cardona.

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
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Image of FIGURE 10
FIGURE 10

Overview of the characteristics of tuberculosis in laboratory animals and humans. Note that these groups overlap because of variations among individual members. Liquefaction, cavity formation, extracellular bacillary multiplication, and bronchial dissemination can overwhelm the hosts in the middle group. CMI, cell-mediated immunity (highly activated macrophages). Caseation, caseous tissue necrosis. Adapted from reference 4. See Table 1 for additional information.

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
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Tables

Generic image for table
TABLE 1

Characteristics of tuberculosis in humans and in laboratory animals a, b

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
Generic image for table
TABLE 2

Characteristics of pulmonary tuberculous lesions in rabbits, mice, and guinea pigs

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15
Generic image for table
TABLE 3

Number of inhaled tubercle bacilli required to produce one primary pulmonary tubercle and the amount of multiplication during the logarithmic growth phase in rabbits, mice, and guinea pigs a

Citation: Dannenberg, Jr. A. 2006. Comparisons of Tuberculosis in Rabbits, Mice, and Guinea Pigs, p 246-269. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch15

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