Nicotine & Immunopathogenesis of Cryptococcal meningitis

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DESCRIPTION (provided by applicant): Opportunistic infections of the central nervous system are common complication in acquired immunodeficiency syndrome (AIDS) patients. Cryptococcus neoformans (Cne) is an encapsulated yeast that causes often fatal cryptococcal meningoencephalitis (CM) in 7-30% of AIDS patients. While highly active anti-retroviral therapy has successfully decreased the incidence of many opportunistic infections, it is less effective in decreasing the incidence of opportunistic fungal infections in advanced AIDS patients. The host's response to Cne is a complex interplay between the innate and adaptive immunities. In animal models, the inability to increase the brain levels of proinflammatory cytokines or promote leukocyte migration into the brain is typically associated with lethal CM. Thus, "proinflammatory" responses are required to contain Cne infection in the central nervous system. Epidemiological studies show that cigarette smoking is a significant risk factor in cryptococcosis and other opportunistic fungal infections, and >85% of AIDS patients with cryptococcosis are cigarette smokers. However, the mechanism by which smoking affects the pathogenesis of Cne is totally unknown. We have demonstrated that cigarette smoke suppresses the immune system, and nicotine (NT) is a major immunosuppressive component of cigarette smoke that causes T cell anergy and inhibits the inflammatory responses. Our preliminary studies suggest that chronic NT treatment inhibits chemokinesis/chemotaxis and the migration of leukocytes to the site of inflammation, decreases brain IL-1beta expression in response to an inflammatory stimuli such as turpentine and Cne, and promotes growth and early dissemination of Cne into the brain. Therefore, we hypothesize that cigarette smoke/NT modulates both the innate and adaptive immune responses to Cne, thus facilitating its dissemination to the brain and the development CM. To test this hypothesis and to identify mechanism(s) by which NT facilitates brain infection by Cne, the following studies are proposed: 1. To investigate the effects of NT on Cne-induced innate immunity, including the expression of proinflammatory cytokines/chemokines in the brain and the response of leukocytes to cytokines/chemokines that are affected by Cne, to establish the kinetics of Cne and leukocyte migration into the brain and the development of CM, and to examine the effects of NT on the Cne-induced fever response. 2. To ascertain the effects on the adaptive immune responses including generation of anti-Cne antibodies, proliferative and delayed-type hypersensitivity responses to cryptococcal antigens, and generation of cytotoxic T cells to immunodominant epitopes of Cne proteins, as well as to evaluate the protective function of T cells that migrate into the brain after Cne infection. 3. To investigate the mechanisms by which NT suppresses the migration of leukocytes toward the site of infection. These studies, we believe, will delineate the mechanism(s) by which smoking/NT encourages dissemination of Cne and, perhaps, other fungal infections into the brain of AIDS patients, and identify potential therapeutic targets for treatment of CM.