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, 98 (3), 324-8

Granuloma Formation Is Required to Contain Bacillus Growth and Delay Mortality in Mice Chronically Infected With Mycobacterium Tuberculosis

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Granuloma Formation Is Required to Contain Bacillus Growth and Delay Mortality in Mice Chronically Infected With Mycobacterium Tuberculosis

B M Saunders et al. Immunology.

Abstract

Previous studies in this laboratory have shown that mice with a gene disruption to the intracellular adhesion molecule-1 (ICAM-K/O) express normal cell-mediated immunity but cannot mount delayed-type hypersensitivity reactions following Mycobacterium tuberculosis infection. However, even in the absence of any appreciable granuloma formation, these mice control bacterial growth for at least 90 days. While not required to control the infection initially, we hypothesized that granuloma formation was required to control chronic infection, acting by surrounding infected cells to prevent bacterial dissemination. To test this, ICAM-1 knockout mice were infected with a low dose aerosol of M. tuberculosis Erdman and were found to succumb to infection 136+/-30 days later, displaying highly elevated bacterial loads compared to wild-type mice. Lung tissue from ICAM-K/O mice displayed extensive cellular infiltration and widespread tissue necrosis, but no organized granulomatous lesions were evident, whereas the control mice displayed organized compact granulomas. These data demonstrate that while a granulomatous response is not required initially to control M. tuberculosis infection, absence of granulomas during chronic infection leads to increased bacterial growth and host death. Thus these data support the hypothesis that granuloma formation is required to control chronic infection, acting by surrounding and walling off sites of infection to prevent bacterial dissemination and maintain a state of chronic infection.

Figures

Figure 1
Figure 1
Survival of M. tuberculosis infected ICAM-K/O mice. Wild-type (□) and ICAM-K/O (▪) mice were infected with ≈100 bacilli via aerosol. Mice were monitored daily for signs of deterioration and moribund mice were killed. Data represent eight mice per group. Mean survival time for ICAM-K/O mice was 136 days and for wild-type mice >270 days.
Figure 2
Figure 2
Representative photomicrographs from lungs of wild-type and ICAM-K/O mice infected for 126 days with M. tuberculosis Erdman. (a) Wild-type mice: note the multiple organized granulomatous lesions composed of a central core of lymphocytes surrounded by epithelioid macrophages, with few neutrophils present. Large sections of normal lung are still present. (b) ICAM-K/O mice: extensive cellular influx throughout the lung, no organized granulomatous structure is visible and very few areas of normal lung are left. (c) Magnification of a granulomatous lesion from the lungs of a wild-type mouse: note the central lymphocyte core surrounded by large epithelioid macrophages. (d) and (e) Magnification of a section of lung from an ICAM-K/O mouse: tissue shows evidence of extensive necrosis, large numbers of neutrophils and degenerative cells are present. Multinucleated giant cells are visible (arrow) as are several cholesterol clefts (arrowheads), only scattered pockets of lymphocytes are evident. (f) Wild-type mice:note the occasional acid-fast bacilli visible within the macrophages. (g) ICAM-K/O mice: note the multiple acid-fast bacilli visible within most macrophages. (a)–(e) were stained with haematoxylin and eosin staining; (f)and (g) were stained with Kinyoun’s stain. Bar equals 1 mm in (a) and (b) and 100 μm in (c)–(g).

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