Elucidating the impact of fungal adhesins on intestinal homeostasis

项目总结/文摘

Project Summary/Abstract The intestinal microbiota regulates many facets of human health, but also harbors commensal microbes that can exacerbate disease. Fungi are excellent examples of commensal organisms with pathogenic potential. Fungi that dominate the intestinal fungal community include Candida species, which are well-known opportunistic fungal pathogens. Candida have also been shown to induce inflammation within the gut that exacerbates inflammatory bowel disease. However, Candida are common colonizers of healthy people where they rarely cause disease. In addition, recent work has suggested that Candida colonization may even be beneficial by inducing immune responses that protect against mucosal and disseminated pathogens. However, the forces that constrain Candida to a commensal lifestyle are largely unknown. Our recent study demonstrated that adaptive immune responses serve an important role in promoting Candida commensalism. We found that intestinal IgA antibodies target and suppress potentially pathogenic Candida effectors, called adhesins, within the gut. Candida adhesins are notorious virulence factors that promote host tissue adherence and invasion, though their role in shaping fungal commensalism in the gut is unknown. For Candida albicans, we found that adhesin expression exacerbates intestinal colitis in mice. We also found that that an adhesin-based vaccine prevents C. albicans-associated pathology. Interestingly however, we found that adhesin expression is associated with reduced C. albicans fitness in the gut. Together, these data suggest that Candida adhesins are important fungal effector molecules that potentially disrupt host and fungal homeostasis in the gut. This proposal will explore the role of fungal adhesins in shaping host immune responses and impacting intestinal colitis. It will leverage an adhesin-based vaccine to explore how adhesin-specific immunity shapes Candida commensalism. This proposal will also use Candida glabrata to identify novel fungal adhesins that regulated intestinal immune responses and colitis. These studies will significantly advance our understanding of protective mechanisms that prevent Candida commensals from becoming pathogenic within the gut. The results of these studies will inform the development of future vaccines aimed at restoring homeostasis with commensal fungi.