Immunological Basis for Reactivation of Tuberculosis in Mice

J Turner

M Gonzalez-Juarrero

B Saunders

J Brooks

Departments of Microbiology^{and Pathology,}^{Colorado State University, Fort Collins, Colorado 80523}

^{Corresponding author. Mailing address: Department of Microbiology, Colorado State University, Fort Collins, CO 80523. Phone: (970) 491-6127. Fax: (970) 491-1815. E-mail:}ude.etatsoloc.sbmvc@renrutJ.

^{Present address: Centenary Institute, Newtown, NSW 2042, Australia.}

Received 2000 Sep 15; Revisions requested 2000 Dec 13; Accepted 2001 Feb 9.

Abstract

In this study different inbred strains of mice appeared to control and contain a low dose aerosol infection with Mycobacterium tuberculosis in a similar manner, giving rise to a chronic state of disease. Thereafter, however, certain strains gradually began to show evidence of regrowth of the infection, whereas others consistently did not. Using C57BL/6 mice as an example of a resistant strain and CBA/J mice as an example of a strain susceptible to bacterial growth, we found that these animals revealed distinct differences in the cellular makeup of lung granulomas. The CBA/J mice exhibited a generally poor lymphocyte response within the lungs and vastly increased degenerative pathology at a time associated with regrowth of the infection. As a possible explanation for these events, it was then observed that the CBA/J mouse strain was also less able to upregulate adhesion molecules, including CD11a and CD54, on circulating lymphocytes. These results therefore suggest that a failure to control a chronic infection with M. tuberculosis may reflect an inability to localize antigen-specific lymphocytes within the lung.

Abstract

Disease caused by Mycobacterium tuberculosis is often not due to primary infection but instead is caused by reactivation of a latent or dormant infection that the patient may have carried for many years (20). It is unclear however, how the host initially expresses resistance in the lung and why this resistance is eventually lost, thus allowing bacterial regrowth. In this regard, the mouse is a useful model of specific resistance to M. tuberculosis infection. After low or moderate doses of bacilli are delivered by either intravenous or aerogenic routes, an apparently stable chronic disease state is established after a few weeks in the infected organs of the animal (3, 24). This chronic infection continues for a prolonged period in the C57BL/6 mouse strain until influenced by immunosenescence (23). It is currently speculated that during the chronic phase of infection, the bacteria remain in some form of latent state.

That this assumption may be wrong, however, is suggested by recent evidence indicating that chronic M. tuberculosis infection in the lung is in fact a dynamic event (27), at least in terms of granuloma pathology, which changes dramatically over the life span of the animal. In addition, studies directed toward understanding the role of the Bcg gene (Nramp1) have shown that certain inbred strains of mice clearly differ in their ability to survive a chronic M. tuberculosis infection (16, 18), in confirmation of much earlier reports of this phenomenon (15, 26).

The results of the current study confirm and extend these findings by showing that certain strains of mice, although able to initially control a low-dose aerosol infection with M. tuberculosis, eventually succumb during the chronic phase of disease. The current study shows that this early mortality was associated with an increased bacterial burden within the lung and occurred prior to events that could be attributed to immunosenesence (23). Comparison of the pathology in reactivation-prone mice and those which were able to maintain the chronic disease state highlighted profound differences as early as the first few weeks into infection. Of these, the most obvious difference was the predominance of macrophages, combined with a minimal lymphocyte influx, within the lesions of the susceptible mouse strains. This absence of lymphocytes was associated with a failure to upregulate the T-cell adhesion molecules CD11a and CD54 on circulating lymphocytes. These data thus imply that strains of mice prone to this regrowth or reactivation phenomenon are less able to recruit lymphocytes to the site of infection and that this inability then predisposes the animal to an increased likelihood of bacterial regrowth at a later time.

ACKNOWLEDGMENTS

This work was supported by NIH grants AI-44072, AI-40488, and AG-06946.

ACKNOWLEDGMENTS

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