Globally, tuberculosis (TB) is the leading cause of death from infectious disease. When infection disseminates from the lungs to the central nervous system (CNS), the mortality of TB, when untreated, approaches 100%. Medical conditions that impair cell-mediated immunity, including HIV infection, foster the development of disseminated TB, whereas immunization with Mycobacterium bovis BCG vaccine confers protection against dissemination to the CNS. Recent studies indicate that immunity against TB is mediated by T lymphocyte subpopulations, which inhibit the growth of the tubercle bacillus within tissue macrophages. Because of morphine's effects on cell-mediated immunity, opiate abuse has been suspected of increasing the susceptibility to TB. However, experimental studies examining whether morphine promotes the pathogenicity of either of the mycobacterial species that cause TB (M. tuberculosis or M. bovis) are lacking. The central hypothesis to be tested in the research proposed is that morphine promotes the immunopathogenesis of disseminated M. bovis infection. To test the hypothesis, both in vitro and in vivo experiments will be conducted using a swine model of disseminated TB.
The specific aims are to: (1) characterize the effect of morphine in vitro on M. bovis infection of microglial cells and monocytes; (2) determine the effect of morphine dependence of non-immunized swine on the growth of M. bovis in microglial cells in vivo, and correlate these histopathologic findings with the clinical course of CNS infection; (3) characterize the effect of morphine in vitro on the anti-M. bovis activity of T lymphocyte subsets obtained from BCG-immunized swine; and (4) determine the effect of morphine in BCG-immunized swine on vaccine protection against CNS TB. Primary cultures of microglial cells and monocytes will be obtained from neonatal pigs. In addition to studying the effects of morphine in vitro on the interaction between M. bovis and these cell populations, the influence of morphine on the anti-mycobacterial activity of T lymphocyte subsets from immunized animals will be determined. A newly developed in vivo swine model of disseminated M. bovis infection will be used. We postulate that morphine administered to non-immunized swine will promote the development of CNS TB, whereas morphine administered to BCG-immunized swine will be associated with loss of the vaccine's protective effect against CNS TB. These studies will, for the first time, provide experimental evidence relevant to the clinical concern that opiate abuse fosters the pathogenesis of TB.
