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: 10353044
• 负责人: Richard John Bennett
• 金额: $ 19.89万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353044
• 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，它在人体内定植多个生态位，包括 皮肤、胃肠道(GI)和泌尿生殖道。然而，这一物种也负责一个品种 粘膜感染和全身感染之间的关系，后者与高死亡率相关。除了……之外 引起机会性疾病的胃肠道真菌定植现在被认为是教育的关键 宿主免疫系统的多个方面。因此，迫切需要了解 白念珠菌共生的机制和确定这种真菌如何调节宿主 免疫反应。 在这项提案中，我们讨论了ECE1在白色念珠菌在胃肠道定植中的作用。这个 ECE1基因产物编码通过全长Kex2处理产生的八个肽 蛋白。第三种Ece1多肽现在被称为假丝酵母毒素--一种直接损害宿主的多肽毒素 上皮细胞，并能激活炎症小体。然而，大多数研究都集中在细胞因子的作用上。 ECE1在体外或口腔感染模型中，目前对该基因是否存在了解有限 影响GI利基中白色念珠菌的生长。 我们的初步数据表明，ECE1在促进白色念珠菌的定植中起着关键作用 肠子里的。此外，ECE1提高适应性的程度取决于所使用的小鼠模型， 在保留完整微生物组(即避免使用抗生素)的模型中，最大的贡献显而易见 补充)。我们将在这些观察的基础上确定假丝酵母多肽或 其他ECE1肽(S)有助于共生健康。我们的研究还将解决Ece1是否 影响细菌微生物群或宿主对白色念珠菌的反应，以及Ece1编码 多肽促进真菌移位到血液中，从而促进全身疾病。 此外，我们还揭示了ECE1等位基因之间存在着显著的序列多样性 来自不同的白色念珠菌分离株。因此，我们将在不同的临床集合中定义ECE1变异 分离并测试序列变异是否会导致共生模型中的功能差异。这些 实验可能会确定ECE1在确定菌株特异性差异方面的作用。 物种。 总之，这些研究将确定ECE1(和念珠菌素)对健康的贡献 白念珠菌细胞在共生的胃肠道生态位，以及宿主对这种真菌的反应。我们期待着 这些实验将扩大我们对使白色念珠菌 定植，包括Ece1在这一重要病原体生物学中的确切作用。