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

定义白色念珠菌念珠菌溶酶在胃肠道生态位中的作用

• 批准号: 10495258
• 负责人: Richard John Bennett
• 金额: $ 23.93万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10495258
• 关键词: Address; Alleles; Antibiotics; Bacterial Infections; Biology; Blood Circulation; Candida; Candida albicans; Cells; Clinical; Collection; Data; Diploidy; Disease; Distal; Education; Epithelial Cells; Exhibits; Future; Gastrointestinal tract structure; Genes; Genetic Transcription; Growth; Human body; Immune response; Immune system; Immunity; In Vitro; Inflammasome; Investigation; Length; Life; Lung; Modeling; Molecular; Mucous Membrane; Mycoses; Oral cavity; Pathogenicity; Peptides; Play; Process; Property; Proteins; Role; Seeds; Sepsis; Sequence Analysis; Skin; Source; Supplementation; Symbiosis; Systemic disease; Systemic infection; Testing; Tissues; Toxin; Variant; Virus Diseases; bacteriome; cytokine; defined contribution; experimental study; fitness; fungus; gastrointestinal; gastrointestinal epithelium; gene product; genomic variation; gut colonization; human microbiota; immune activation; improved; in vivo; intestinal injury; microbiome; mortality; mouse model; opportunistic pathogen; oral infection; pathobiont; polypeptide; response; urogenital tract

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.

项目摘要 白色念珠菌是一种病原体，在人体中的多个壁nir中殖民 皮肤，胃肠道（GI）和泌尿生殖道。但是，该物种也负责多种多样 粘膜和全身感染，后者与高死亡率相关。此外 引起机会性疾病，胃肠道的真菌定植被认为对教育至关重要 宿主免疫系统的多个方面。因此，有迫切需要了解 白色念珠菌共同体的机制，并确定这种真菌如何调节宿主 免疫反应。 在此提案中，我们解决了ece1在白色念珠菌在胃肠道定植中的作用。这 ECE1基因产物编码八个Petides，它们是通过全长处理的Kex2加工生成的 蛋白质。现在，第三个ECE1肽被称为念珠菌素 - 一种直接损害宿主的肽毒素 上皮细胞并可以激活炎症体。但是，大多数研究都集中在 ECE1体外或口服感染模型，目前对此基因的了解有限 影响胃肠道的白色念珠菌生长。 我们的初步数据确定ECE1在促进白色念珠菌定植中起关键作用 肠道。此外，ECE1提高健身的程度取决于所使用的鼠模型， 保留完整微生物组的模型中最大的贡献元素（即避免抗生素 补充）。我们将基于这些观察，以确定念珠菌素胡椒还是 其他ECE1胡椒（S）有助于共同适应性。我们的研究还将解决ECE1是否 影响细菌微生物组或宿主对白色念珠菌的反应，以及ECE1编码是否 肽可促进真菌易位进入血液，从而促进全身性疾病。 此外，我们揭示了ECE1等位基因之间存在显着的序列多样性 来自不同白色念珠菌分离株。因此，我们将定义临床收集的潜水员集合中的ECE1变化 分离株并测试序列变化是否导致共生模型的功能差异。这些 实验将有可能确定ECE1在确定应变特异性差异中的作用 物种。 这些研究将共同​​确定ECE1（和Candidalysin）对健身的贡献 在共生胃肠道中的白色念珠菌细胞以及对这种真菌的宿主反应。 这些实验将扩大我们对能够使白色念珠菌的真菌因素的理解 定植，包括ECE1在这一重要病原体生物学中的精确作用。