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Chapter 7 : Mouse and Guinea Pig Models of Tuberculosis

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Abstract:

Small-animal models have provided a vast amount of useful information about the nature of tuberculosis infection and its pathogenesis, the host response to it, and the activity of potential new vaccines and drugs. While it is possible that central mechanisms would have been eventually discovered directly in humans, there is no doubt that much of what we know about the immune response to the disease was substantially accelerated by studies in the mouse model, which took direct advantage of the literal explosion in the availability of reagents developed by the mainstream immunology field over the past 3 or so decades. These advances have allowed us to define in great detail the nature of the T-cell response to and its various elements, including control of activation and cellular recruitment by cytokines and chemokines, as well as more practical applications in the form of using this inexpensive model to test vaccines and drugs.

Citation: Orme I, Ordway D. 2017. Mouse and Guinea Pig Models of Tuberculosis, p 143-162. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0002-2015
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Figure 1

Commonly used devices for aerosol exposure of mice and guinea pigs. Glas-Col aerosol exposure device. The exposure cage is placed into the central chamber of the machine and closed from above by a tight gasket; this cage can hold approximately 100 mice at a time. The famous “Madison Chamber” first designed at the University of Wisconsin. The central chamber holds up to 18 guinea pigs at a time. The Henderson apparatus, which is a “nose-only” aerosol exposure device. This system can be readily used for infections of both mice and guinea pigs. (Photo courtesy of Ann Williams, with permission.)

Citation: Orme I, Ordway D. 2017. Mouse and Guinea Pig Models of Tuberculosis, p 143-162. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0002-2015
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Image of Figure 2
Figure 2

Representative data from the mouse after low-dose aerosol exposure to ∼100 (in these examples, H37Rv). After about 30 days of progressive growth the infection is controlled and contained. There follows what many regard as a “chronic phase” during which some animals may start to die of lung damage. Influx of CD4 cells, which comprise the bulk of the T-cell response, and CD8 cells. A fraction of the total CD4 cell numbers stain positive for IFN-γ, and the numbers of these steadily contract after day 30 as the course of the infection is controlled. Immunohistochemical identification of CD4 and CD8 cells in lung granulomatous tissue. CD4 cells tend to spread evenly across the lesions, whereas CD8 cells take up a more peripheral position. (Photos courtesy of O. Turner, with permission.)

Citation: Orme I, Ordway D. 2017. Mouse and Guinea Pig Models of Tuberculosis, p 143-162. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0002-2015
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Figure 3

Other characteristics of the lung inflammatory response. The response to low-dose aerosol infection also includes the influx of aggregates of B cells (left) and small numbers of γδ+ T cells (right). Early during the course of the infection, cells can be seen interacting or adhering to the airway epithelial surface (left), but, as the disease process continues, this surface swells and degenerates (right). (Photos courtesy of O. Turner and M. Gonzalez-Juarrero, with permission.)

Citation: Orme I, Ordway D. 2017. Mouse and Guinea Pig Models of Tuberculosis, p 143-162. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0002-2015
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Figure 4

Some newly emerging strains of induce the appearance of regulatory T cells in the lungs. These can be identified and gated using flow cytometry because of their intracellular expression of the Foxp3 marker. Usually, approximately 50% of these cells are capable of secreting the cytokine IL-10.

Citation: Orme I, Ordway D. 2017. Mouse and Guinea Pig Models of Tuberculosis, p 143-162. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0002-2015
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Figure 5

Immunopathology of the guinea pig model. After 5 to 10 days after aerosol infection, small lesions appear, usually near larger airways. These consist mostly of macrophages, with a few lymphocytes and neutrophils beginning to arrive. By day 15 to 20 the lesion has become much larger and the first signs of central necrosis are visible. By day 30 to 40 the lesion has the appearance of the “classical granuloma,” with a large central area of necrosis obvious and with host cells remaining viable being compressed outward. Thereafter, the lesion becomes very large and is dominated by a process of central dystrophic calcification (this entire process is described in greater detail in reference ). (Photos courtesy of O. Turner.) More recently, we have attempted to explain this process in a “unifying theory” to relate it to reactivation disease (see reference ). In our current working model, the infecting bacilli use their ESX proteins to escape the alveolar macrophage that engulfed them and reach the interstitium, which swells with tissue fluid due to the inflammation Macrophages, dendritic cells, lymphocytes, and neutrophils accumulate at this new site of infection The dendritic cells carry bacilli (or antigen secreted by them) off to the draining lymph node (a crucial event in generating acquired immunity), while (we propose) the local neutrophils degenerate and hence trigger the beginnings of the development of necrosis. Gradually, the lesion takes on its characteristic appearance, as the central lesion first starts to calcify By now, many bacteria are extracellular, and some (we now believe based on recent new evidence) survive by becoming nonplanktonic and acid-fast-negative small communities. As the lesion calcifies, some of these communities get physically forced back toward normoxic tissue , where they may be recognized by host cells and trigger memory immunity. If this is not successfully dealt with, reactivation disease ensues, with the potential that some bacilli escape into the airway and can be potentially transmitted (Photos in panels A to D courtesy of O. Turner, reprinted from reference . Panels E to I adapted from reference .)

Citation: Orme I, Ordway D. 2017. Mouse and Guinea Pig Models of Tuberculosis, p 143-162. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0002-2015
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Figure 6

A new approach to gating host cells harvested from the guinea pig lung. The major impediment caused by severe autofluorescence in this model can be subverted by gating side scatter against the antibody MIL4. This reveals otherwise “hidden” lymphocytes, macrophages, and monocytes, while still allowing enumeration of the granulocyte response. DC, dendritic cells; SSC, side scatter.

Citation: Orme I, Ordway D. 2017. Mouse and Guinea Pig Models of Tuberculosis, p 143-162. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0002-2015
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Figure 7

Characteristics of the guinea pig response to infection. After exposure to 10 to 20 bacilli, between 5-log and 6-log can be detected in all three major target organs after a month. There are strong CD4 and CD8 responses initially, but these then contract after ∼30 days. There is a strong and progressive influx of macrophages into the lungs, but only a small percentage of these appear to be activated (class II MHC). After day 30 or so, significant numbers of B cells begin to arrive, as do neutrophils, presumably responding to the lung damage. (Adapted from reference .)

Citation: Orme I, Ordway D. 2017. Mouse and Guinea Pig Models of Tuberculosis, p 143-162. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0002-2015
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Figure 8

Magnetic resonance imaging of infected guinea pig lungs. A day-30 image showing obvious lesions with transparent central necrosis (“doughnut appearance”; not obvious using other imaging methods). Severe lymphadenopathy, which occurs rapidly, is readily seen by MRI. Day-30 imaging prior to treatment for the next 4 months with chemotherapy, resolving most of the lesions , in comparison with untreated animals in which the lungs eventually become almost completely consolidated (Photos courtesy of Susan Kraft. Adapted from reference .)

Citation: Orme I, Ordway D. 2017. Mouse and Guinea Pig Models of Tuberculosis, p 143-162. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0002-2015
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