The lung is the portal of entry for many important fungal pathogens including Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. Mechanisms of host defense against fungal pathogens are poorly understood. In particular we know very little about the role of antibody-mediated immune responses in either the protection against or the pathogenesis of infection. The question of how antibody participates in lung defense is important for both the fundamental understanding of host defense mechanisms and the practical goals of vaccine design. Antibody responses to fungal antigens could, in theory, be protective, deleterious, or irrelevant to the host. Recently, this laboratory has shown that antibody administration protects against pulmonary C. neoformans infection in mice. Studies of lung tissue response in antibody-treated and control mice suggests that antibody functions enhancing cellular immunity in the lung. This application proposes to explore mechanisms by which antibody and cellular immunity collaborate and cooperate against microorganisms in the lung.
Three specific aims are proposed: 1. To determine the role of Th1- and Th2-associated cytokines in antibody-mediated protection against pulmonary C. neoformans infection; 2. To determine the relationship between antibody-mediated protective effects in the lung and nitric oxide production; and 3. To determine the effect of polysaccharide-protein conjugate vaccination on pulmonary defenses against C. neoformans in the context of cytokine- and nitric oxide-related mechanisms.
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