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Chapter 8 : Mouse Model of Tuberculosis

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Abstract:

This chapter describes how the mouse model has evolved over the past century from the simple but beautiful experiments of Koch to present-day models based on sophisticated gene targeting. In the process, the authors describe the course of the infection in the mouse after inoculation by various routes and their growing picture of how the host immune response is mobilized against the infecting organism. They also describe various mouse models that involve immunodeficiency; these may prove useful not only in the further dissection of the cellular immune response but also in applied strategies of chemotherapy and immunotherapy. The growth of in mice has been extremely well characterized, with the organism giving rise to highly characteristic distribution patterns in target organs after inoculation. A week or so after inoculation of mice with a sublethal intravenous dose of , a population of CD4 cells that are capable of adoptively transferring protective immunity emerges in the spleen. In the mouse model of tuberculosis, enriched populations of immune CD8 T cells transferred some degree of resistance, albeit rather weakly, and in vivo depletion of CD8 T cells by intravenous administration of monoclonal antibody was shown to diminish resistance to some extent. The cytokine response to probably begins almost immediately after infection of host macrophages, as these cells begin to transcribe message from a number of early response genes.

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 1

Course of infection in mice given 10 viable bacilli intravenously. The infection grows quickly in the spleen over the first 10 to 14 days, triggering the emergence of protective immunity. The liver is more resistant to the infection; it does not permit rapid growth initially and continues to slowly clear the infection (in contrast, the disease remains chronic in both the spleen and lungs). Note the characteristic distribution of the inoculum: about 90% is taken up in the liver, about 10% is taken up in the spleen, and about 1% is taken up in the lungs (uptake that exceeds 5% in the lungs is a sure sign that the inoculum is clumped).

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Image of Figure 2
Figure 2

Course of infection in mice given approximately 20 viable bacilli by aerosol. The infection progresses in the lungs over the first 20 to 30 days before being contained by the emerging immune response. At around this time, significant numbers of bacteria can be detected in the spleen (and liver); these bacilli probably arose from a few organisms that eroded early from the lungs into the bloodstream (hematogenous spread).

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 3

Intravenous injection of mice. Following warming under a heat lamp for a few minutes to induce vasodilation, the mouse is gently positioned in this simple restraining device. The bacterial inoculum is injected into a lateral tail vein with a 26-gauge needle.

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 4

Aerosol infection of mice. The venturi unit at the front of the generator creates an aerosol that is pumped into a central sealed chamber containing the animals. The operator is wearing a Racal AC3 helmet for added protection (this device includes a small HEPA filter, worn on a waist belt, that blows sterilized air up and through the helmet). The aerosol generator suite is negative with respect to atmospheric pressure, and all air leaving the room is HEPA filtered.

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 5

The potential fate of immune CD4 T cells. Sensitized protective T cells release cytokines (IFN-γ, migration inhibition factor, TNF, etc.) that activate the parasitized macrophage to contain the intracellular infection. In addition, these materials recruit monocytes into the lesion to initiate granuloma formation. We currently speculate that memory T cells arise from the same lineage but express a longer-lived phenotype as a result of emigration from the infectious site. Of course, it is equally possible that memory cells arise from a completely separate lineage. This issue remains to be resolved.

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 6

Possible role of CD8 T cells. These cells become sensitized by presentation of mycobacterial antigens in association with class I MHC molecules. As the infection progresses in the lungs, these cells may play a vital role in releasing bacteria that have eroded into local tissues (such as the lung endothelial cells). This speculative model is based on the work of Flynn and her colleagues ( ).

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 7

Mouse macrophage containing several intact bacterial particles. The apparent paradox whereby the bacteria are healthy and intact yet strong immunity can be generated can be explained by the hypothesis that the macrophage is presenting secreted/export proteins of the bacillus rather than constitutive proteins. The ability of the bacilli to survive under such conditions is also a matter of debate; recent data (Sturgill-Koszycki et al., submitted) now suggests that the mycobacteria have an unknown property that prevents the fusion of proton-ATPase complex-containing vesicles to the bacterial phagosome, thus preventing acidification of this compartment. (Photo courtesy of David Russell.)

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 8

Culture filtrate proteins of Erdman. This protein pool contains multiple targets of IFN-γ-secreting protective CD4 T cells harvested from infected mice. Note the differing protein content depending on whether the filtrate is harvested at mid-log phase (M) or several days earlier (short-term filtrate; S). Numbers at right are molecular sizes in kilodaltons. (Courtesy of John Belisle.)

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 9

IFN-γ and IL-4 responses by CD4 T cells to antigens. In this experiment, CD4 T cells were harvested from infected mice at the times indicated and overlaid in vitro on macrophages presenting filtrate protein antigens. Three days later, the supernatants were harvested and tested for IFN-γ or IL-4 by enzyme-linked immunosorbent assay. These data indicate that the CD4 response consists of an early Th1-like response associated with containment and initial clearance of the infection followed after about a month by the emergence of a Th2-like response that presumably drives the humoral response to dead bacteria. In addition, while the Th1 response seems to be preferentially directed against the secreted/export proteins, the Th2 response is broader, including strong recognition of the hsp60 antigen (see text).

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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Figure 10

CD4 T-cell depletion of thymectomized mice by in vivo administration of monoclonal antibody. One injection of 250 μg of highly purified anti-CD4 (clone GK1.5) almost completely eliminates the host CD4 T-cell population. The data are expressed as contour maps following analysis of CD3CD4 cells in the spleen by flow cytometry. FITC, fluorescein isothiocyanate.

Citation: Orme I, Collins F. 1994. Mouse Model of Tuberculosis, p 113-134. In Bloom B (ed), Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555818357.ch8
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