Fungal infections in general and Candida albicans infections in particular are important causes of morbidity and mortality in immunocompromised individuals. This study will evaluate a novel antifungal mechanism by which lymphocytes directly interact with and affect C. albicans. The role of lymphocytes in host protection from fungal infection has been thought to be primarily the elaboration of cytokines that produce effects upon phagocytic cell populations. More recently, lymphocytes have been demonstrated to interact directly with fungi and to exert an antifungal effect. It is the purpose of this investigation to delineate the process by which lymphocytes adhere to, are activated by, and produce an antifungal effect against the hyphal and yeast forms of C. albicans.
The specific aims of this project are: 1) Determine the means by which lymphocytes adhere to C. albicans hyphae and yeast. 2) Identify the process by which lymphocytes are activated by and introduced to undergo cytoplasmic granule exocytosis by C. albicans hyphae and yeast. 3) Determine the antifungal effect of lymphocytes and lymphocyte cytoplasmic granules on C. albicans. This study is timely in that the numbers of immunocompromised individuals has dramatically increased in recent years. Immunocompromised individuals at greatest risk for fungal infections are: patients with cancer; those undergoing organ transplantation; diabetics; those on long-term corticosteroid therapy; those at risk for hospital acquired infection; and those with the acquired immune deficiency syndrome. Attributable mortality is high with the emergence of increasingly severe fungal disease. C. albicans has an occult presentation and is not only difficult to diagnose but also to treat. It has been difficult to understand the means by which the mammalian host deals with C. albicans. Lymphocytes may provide an important host defense mechanism by which to limit C. albicans. Such a form of antifungal defense may become important when host defense mechanisms are disrupted. This study will establish the cellular and molecular mechanisms by which lymphocytes directly interact with and inhibit the growth of C. albicans. Elucidation of these mechanisms will precisely describe an alternative, and as yet undescribed means by which lymphocytes may serve to protect the host from fungi. This precise description will impact the increasingly large numbers of individuals who, due to immunocompromise, are beset by fungal disease. The focus of this work is upon C. albicans, but the elucidation of these cellular and molecular mechanisms should contribute significantly to the understanding of lymphocyte interactions with and growth inhibition of other clinically important fungi as well. This investigation is an important experimental link in the process of understanding the host protective response to opportunistic microbial pathogens. As such it will provide information about a new and possibly important means by which to protect immunocompromised individuals from clinically relevant fungal infection.
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