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 白色念珠菌是一种致病菌，在人体内的多个壁龛中定植，包括 皮肤、胃肠道（GI）和泌尿生殖道。然而，这个物种也负责各种 粘膜和全身感染，后者与高死亡率有关。除了 导致机会性疾病，真菌定植的胃肠道现在被视为是至关重要的教育 宿主免疫系统的多个方面。因此，迫切需要了解 C.白念珠菌寄生，并确定这种真菌如何调节宿主 免疫反应。 在这个提议中，我们解决了ECE 1在C.白色念珠菌。的 ECE 1基因产物编码八种肽，这些肽是通过Kex 2加工全长ECE 1基因产生的。 蛋白第三种Ece 1肽现在被称为Ecedalysin--一种直接损害宿主的肽毒素 上皮细胞，并能激活炎性小体。然而，大多数研究都集中在 ECE 1在体外或口腔感染模型中的表达，目前对该基因是否 影响C。白色念珠菌生长在胃肠道利基。 我们的初步数据表明，ECE 1在促进C.白色念珠菌定植 的内脏。此外，ECE 1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的模型中明显的最大贡献（即，避免抗生素 补充）。我们将建立在这些观察，以确定是否有β-dalysin肽或 其它的Ece 1肽有助于骨骼健康。我们的研究还将探讨Ece 1 影响细菌微生物组或宿主对C.白色念珠菌，以及是否Ece 1编码 肽促进真菌移位进入血流，从而促进系统性疾病。 此外，我们还揭示了ECE 1等位基因之间存在着显著的序列多样性 不同的C。白色念珠菌分离株。因此，我们将在一个不同的临床集合中定义ECE 1变异。 分离并测试序列变异是否会导致生物模型中的功能差异。这些 实验将潜在地建立ECE 1在确定菌株特异性差异中的作用， 物种 总之，这些研究将确定ECE 1（和放线菌素）对适应性的贡献。 梭白念珠菌细胞在胃肠道生态位，以及宿主对这种真菌的反应。我们预计 这些实验将扩大我们对真菌因素的理解，使C。白色 殖民化，包括Ece 1在这一重要的致病生物学中的确切作用。