To Define the Role of C. albicans Candidalysin in the Gastrointestinal Niche

点击翻译按钮获取中文摘要

Project Summary Candida albicans is a pathobiont that colonizes multiple niches in the human body including the skin, gastrointestinal (GI) tract and urogenital tract. However, this species is also responsible for a variety of mucosal and systemic infections, with the latter associated with high rates of mortality. In addition to causing opportunistic disease, fungal colonization of the GI tract is now seen as being critical for education of multiple aspects of the host immune system. There is therefore a pressing need to understand the mechanisms underlying C. albicans commensalism and to determine how this fungus modulates host immune responses. In this proposal, we address the role of ECE1 in colonization of the GI tract by C. albicans. The ECE1 gene product encodes for eight peptides that are generated via Kex2 processing of the full-length protein. The third Ece1 peptide is now known as Candidalysin – a peptide toxin that directly damages host epithelial cells and can activate the inflammasome. However, most studies have focused on the role of ECE1 in in vitro or oral infection models and there is currently limited understanding of whether this gene impacts C. albicans growth in the GI niche. Our preliminary data establishes that ECE1 plays a key role in promoting C. albicans colonization of the gut. Moreover, the extent to which ECE1 elevates fitness depends on the murine model used, with the greatest contribution evident in models that retain an intact microbiome (i.e., avoid antibiotic supplementation). We will build on these observations to determine whether the Candidalysin peptide or other Ece1 peptide(s) contribute to commensal fitness. Our studies will also address whether Ece1 impacts the bacterial microbiome or host responses to C. albicans, as well as whether Ece1-encoded peptides promote fungal translocation into the bloodstream and thereby facilitate systemic disease. Furthermore, we reveal that a remarkable level of sequence diversity exists between ECE1 alleles from different C. albicans isolates. We will therefore define ECE1 variation in a diverse collection of clinical isolates and test whether sequence variation results in functional differences in commensal models. These experiments will potentially establish a role for ECE1 in determining strain-specific differences in the species. Together, these studies will determine the contribution of ECE1 (and Candidalysin) to the fitness of C. albicans cells in the commensal GI niche, as well as to the host response to this fungus. We anticipate that these experiments will expand our understanding of the fungal factors that enable C. albicans colonization, including the precise role of Ece1 in the biology of this important pathobiont.