The CDC has estimated that the incidence of fungal infections has increased by 500-fold since 1980. Candida albicans, a common opportunistic fungal pathogen, is the leading cause of invasive fungal disease in immunocompromised individuals;is the major cause of in-hospital infections;and accounts for 20% of all infective endocarditis, which has a mortality rate as high as 70%. The induction of cell-mediated immunity to C. albicans is critical in host defense and the prime task of cells of the innate immune system. Previously, it has been demonstrated that the integrin 1M22 (CD11b/CD18) is the major neutrophil (PMN) receptor involved in C. albicans recognition. The applicant has shown that an activity is released from C. albicans that inhibits PMN adhesion and migration to the fungus. Utilizing two independent affinity approaches, the same single protein responsible for these activities was purified and identified unequivocally as pH-regulated Antigen 1 (Pra1p), also known as Fibrinogen Binding Protein 1, Fbp1, by mass spectrometry and amino acid sequence. Purified Pra1p blocked PMN adhesion to the fungus and prevented PMN-mediated killing of Pra1p-expressing, but not of Pra1p-deficient strains of C. albicans. We hypothesize that the 1M22-Pra1p- fibrinogen interactions are pivotal in C. albicans pathogenesis: fungal-bound Pra1p is a main target of PMN on C. albicans;the soluble form of Pra1p serves as decoy to assist the fungus in escaping host surveillance;and fibrinogen, which interacts not only with Pra1p but also with 1M22, modulates the interactions. To test this hypothesis, the biological significance of these interactions will be assessed in PMN killing assays and in vivo murine models of systemic candidiasis utilizing C. albicans strains, which lack Pra1p and transgenic mice which lack 1M22, and a closely related integrin 1X22 (Aim 1). The effects of soluble Pra1p on these responses will be assays in vitro and in vivo (Aim 2). The role of fibrinogen as a modulator will be investigated biochemically and using mice in which the fibrinogen binding site for 1M22 has been disrupted (Aim 3). The mechanism underlying these interactions will be defined by identifying sites in 1M22 and in C. albicans which mediate their engagement (Aim 4). These studies will provide insights into the basic mechanism underlying C. albicans interactions with the host and may elucidate new strategies to control fungal infections.
Polymorphonuclear leukocytes have been shown to be the primary components of the host's innate immune defenses against C. albicans infections, and the most prominent receptor that they utilize in microbial recognition is integrin 1M22. The applicant has identified Pra1p as the major ligand of 1M22 among fungal proteins. The proposed study will investigate the molecular mechanism of 1M22 - Pra1p interactions in models ex vivo and in vivo in transgenic mice. Data from this study are expected to highlight mechanisms which are involved in fungal-host interactions and to help design new antifungal peptides.
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