Elucidating the impact of fungal adhesins on intestinal homeostasis

项目摘要/摘要 肠道微生物区系调节人类健康的许多方面，但也为 会加重疾病的共生微生物。真菌是共生的很好的例子。 具有致病潜力的生物。主宰肠道真菌群落的真菌 包括念珠菌，这是众所周知的机会性真菌病原体。念珠菌有 也被证明在肠道内引起炎症，从而加剧肠炎。 疾病。然而，念珠菌是健康人的常见殖民者，很少引起 疾病。此外，最近的研究表明，念珠菌的定植甚至可能是 通过诱导免疫反应来保护粘膜和播散性 病原体。然而，约束念珠菌共生生活方式的力量主要是 未知。我们最近的研究表明，获得性免疫反应对 在促进假丝酵母菌共生方面的作用。我们发现肠道中的IgA抗体靶向和 在肠道内抑制可能致病的念珠菌效应物，称为粘附素。念珠菌 粘附素是臭名昭著的毒性因子，可以促进宿主组织的黏附和侵袭， 尽管它们在肠道内形成真菌共生关系中的作用尚不清楚。对于白色念珠菌来说， 我们发现粘附素的表达会加剧小鼠的肠结肠炎。我们还发现， 一种基于粘附素的疫苗可以预防白色念珠菌相关的病理。然而，有趣的是，我们 研究发现，粘附素的表达与白色念珠菌在肠道中的适合性降低有关。 总之，这些数据表明念珠菌粘附素是重要的真菌效应分子。 这可能会破坏肠道内宿主和真菌的动态平衡。这份提案将探讨其作用 真菌粘附素在塑造宿主免疫反应和影响肠结肠炎中的作用。会的 利用粘附素疫苗探索粘附素特异性免疫如何塑造念珠菌 共生主义。这项提议还将使用光滑假丝酵母来鉴定新的真菌粘附素 调节肠道免疫反应和结肠炎。这些研究将大大推进 我们对防止假丝酵母菌共生的保护机制的理解 肠道内致病的。这些研究的结果将为未来的发展提供参考 旨在恢复共生真菌的动态平衡的疫苗。

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.