Cell surface adhesins mediate the first interactions of fungi with mammalian hosts, so adhesin-mediated binding is a prelude to differentiation, colonization, biofilm formation and pathogenic invasion. These events in turn lead to complications of morbidity and mortality, especially common in immunocompromised and chronic disease patients. The C. albicans Als adhesins are implicated in pathogenesis and biofilm formation. They bind to mammalian tissues, cause fungal cell aggregation, and also co-aggregate with other microbial pathogens to mediate polymicrobial infections. Als adhesins are also important in formation of persistent and drug-resistant biofilms in tissues and on indwelling devices. Our long-term goal is to understand the roles for cell adhesion proteins in fungal life cycles and pathogenesis. The central hypothesis of this proposal is that amyloid-forming sequences are a feature of biofilm-forming adhesins, and these sequences potentiate adhesion, fungal aggregation and host invasion. This hypothesis is based on our findings that Als5p causes adherence with amyloid-like features, that the purified Als5p can form authentic amyloids, and that bioinformatic analyses reveal amyloid-forming sequences in many biofilm-associated microbial adhesins.
Three specific aims will test the amyloid/ biofilm hypothesis: (1) To determine the role of specific sequences in amyloid formation and microbial adherence, we will test the working hypothesis that the amyloid-forming sequences are essential for Als-mediated cellular aggregation. (2) We will test the hypothesis that these amyloid-forming sequences in Als proteins are essential for Als-initiated biofilm formation. (3) In Als proteins, glycosylated tandem repeats follow the amyloid-forming sequences, and these repeats greatly increase adhesion activity. We will therefore test the hypothesis that the peptide sequences and glycosylation patterns in the Als repeats modulate amyloid formation to promote cellular aggregation and biofilm formation. The proposed work is innovative in its conjunction of two important concepts: amyloid-like protein interactions and adherence of pathogens leading to biofilm formation. We are also the first group to work on structure and function of Thr-rich repeat sequences in pathogenic and other fungal adhesins. Completion of these aims will lead to better defined models for the initial events in biofilm formation, and will discover whether amyloid-forming sequences are essential for biofilm adherence in fungi. If the hypothesis is supported, the results will establish connections between searches for anti-biofilm and anti-amyloid therapeutic agents.
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