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.

项目概要/摘要 肠道微生物群调节人类健康的许多方面，但也蕴藏着 可以加剧疾病的共生微生物。真菌是共生的绝佳例子 具有致病潜力的生物体。在肠道真菌群落中占主导地位的真菌 包括念珠菌属物种，它们是众所周知的机会性真菌病原体。念珠菌有 还被证明会诱发肠道内炎症，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，很少引起疾病 疾病。此外，最近的研究表明念珠菌定植甚至可能是 通过诱导免疫反应来预防粘膜和播散，从而有益 病原体。然而，限制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，适应性免疫反应发挥着重要作用 促进念珠菌共生的作用。我们发现肠道 IgA 抗体靶向并 抑制肠道内潜在致病性念珠菌效应物，称为粘附素。念珠菌属 粘附素是众所周知的毒力因子，可促进宿主组织粘附和侵袭， 尽管它们在塑造肠道真菌共生中的作用尚不清楚。对于白色念珠菌， 我们发现粘附素的表达会加剧小鼠的肠结肠炎。我们还发现 基于粘附素的疫苗可预防白色念珠菌相关的病理。然而有趣的是，我们 发现粘附素表达与肠道白色念珠菌适应性降低有关。 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稳态。该提案将探讨角色 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。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 共栖主义。该提案还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。这些研究将显着推进 我们对防止念珠菌共生体变成的保护机制的理解 肠道内致病。这些研究的结果将为未来的发展提供信息 旨在恢复共生真菌体内平衡的疫苗。