Infection with the human immunodeficiency virus leads to a systemic immunosuppression that results in an increase in the susceptibility of the host to infection. Infection by opportunistic pathogens is responsible for the morbidity and mortality associated with AIDS. The incidence of mycobacterial diseases, including infections caused by M tuberculosis and avium, has increased significantly among HIV-infected individuals. Studies in the investigator's laboratory have correlated differences in MHC class II expression with resistance to mycobacterial growth in mice. Similar differences in MHC class II expression by human monocytes have been identified also by the investigators. Stress may be an important cofactor in susceptibility to mycobacterial disease, and this laboratory has shown that restraint stress results in a suppression of Ia expression. Differences in Ia expression indicate that there may be differences in the level of activation of the macrophages in mice that are resistant or susceptible to mycobacterial growth. The purpose of this renewal application will be to determine the role of stress in modulating the pathogenesis of mycobacterial infection and to correlate these differences to changes in Ia expression. Thus, restraint stress may alter the host parasite relationship by allowing the opportunistic pathogen to become established and grown within mononuclear phagocytes.
The specific aims are: (1) to determine the effect of restraint on the growth of Mycobacteria in vivo; (2) to determine whether restraint stress induced alteration in mycobacterial growth is mediated by the hypothalamic-pituitary-adrenal axis; (3) to determine the role of the sympathetic nervous system in restraint stress mediated alteration in mycobacterial growth; (4) to determine the effect of restraint stress on the in vitro activity of macrophages; and (5) to determine the mechanism of restraint stress mediated alteration in macrophage function.
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