Elucidating the impact of fungal adhesins on intestinal homeostasis

阐明真菌粘附素对肠道稳态的影响

• 批准号: 10429262
• 负责人: Kyla Ost
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429262
• 关键词: Adherence; Adhesives; Animals; Antibodies; B-Lymphocytes; Bacterial Adhesins; Biology; Candida; Candida albicans; Candida glabrata; Clinical; Colitis; Collection; Communities; Data; Development; Disease; Epitopes; Evolution; Foundations; Future; Gene Expression; Genes; Germ-Free; Goals; Health; Homeostasis; Human; Immune; Immune Targeting; Immune response; Immune system; Immunity; Immunization; Immunoglobulin A; Infection; Inflammation; Inflammatory Bowel Diseases; Intestines; Life Style; Mediating; Molecular; Mucous Membrane; Mus; Organism; Pathogenicity; Pathologic; Pathology; Persons; Play; Process; Proteins; Reagent; Research Personnel; Role; Shapes; Surface; Symbiosis; T-Lymphocyte; Testing; Therapeutic; Tissues; Vaccination; Vaccines; Virulence Factors; Work; adaptive immune response; base; cell type; commensal microbes; design; dextran sulfate sodium induced colitis; fitness; fungus; genome sequencing; gut microbiota; human disease; immunogenic; immunoregulation; improved; intestinal homeostasis; member; microorganism; murine colitis; novel; pathogen; pathogenic fungus; prevent; response; tool; whole genome

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.

项目总结/摘要 肠道微生物群调节着人类健康的许多方面，但也为人类健康提供了一个良好的环境。 会使疾病恶化的微生物。真菌是真菌的极好例子 具有致病潜力的微生物。占肠道真菌群落主导地位的真菌 包括假丝酵母属物种，它们是公知机会性真菌病原体。念珠菌具有 也被证明会诱发肠道内的炎症，从而加剧肠道炎症 疾病然而，念珠菌是健康人的常见定植者，它们很少引起 疾病此外，最近的研究表明，念珠菌定植甚至可能是 通过诱导免疫反应，保护免受粘膜和播散性感染， 病原体然而，将念珠菌限制在一个单一的生活方式的力量主要是 未知我们最近的研究表明，适应性免疫反应是一个重要的 促进念珠菌性尿道炎。我们发现，肠道伊加抗体的目标， 抑制肠道内的潜在致病性念珠菌效应物，称为粘附素。念珠菌 粘附素是促进宿主组织粘附和侵袭的臭名昭著的毒力因子， 尽管它们在肠道中形成真菌寄生虫病中的作用尚不清楚。对于白色念珠菌， 我们发现粘附素的表达加重了小鼠的肠结肠炎。我们还发现， 基于粘附素的疫苗预防C.白色念珠菌相关病理学。有趣的是，我们 发现粘附素表达与C.肠道中的白色念珠菌 总之，这些数据表明念珠菌粘附素是重要的真菌效应分子 可能破坏宿主和真菌在肠道内的体内平衡。本提案将探讨 真菌粘附素在塑造宿主免疫反应和影响肠道结肠炎中的作用。它将 利用基于粘附素的疫苗探索粘附素特异性免疫如何塑造念珠菌 奴隶制。这项建议也将使用光滑念珠菌来鉴定新型真菌粘附素 调节肠道免疫反应和结肠炎。这些研究将大大推进 我们对防止念珠菌感染的保护机制的理解 在肠道内致病。这些研究的结果将为未来的发展提供信息。 疫苗旨在恢复体内平衡与真菌。