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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要白色念珠菌是一种致病生物，它定植于人体的多个生态位，包括皮肤、胃肠 (GI) 道和泌尿生殖道然而，该物种还负责多种。粘膜和全身感染，后者除了与高死亡率相关。引起机会性疾病，胃肠道的真菌定植现在被认为对教育至关重要因此，迫切需要了解宿主免疫系统的多个方面。白色念珠菌共生机制的基础，并确定这种真菌如何调节宿主免疫反应。在本提案中，我们讨论了 ECE1 在白色念珠菌胃肠道定植中的作用。 ECE1 基因产物编码八种肽，这些肽是通过全长的 Kex2 处理生成的第三种 Ece1 肽现在被称为念珠菌溶酶 - 一种直接宿主损伤的肽毒素。然而，大多数研究都集中在上皮细胞的作用上。 ECE1 体外或口腔感染模型，目前对该基因是否存在了解有限影响白色念珠菌在胃肠道生态位中的生长。我们的初步数据表明，ECE1 在促进白色念珠菌定植中发挥着关键作用此外，ECE1 提高适应性的程度取决于所使用的小鼠模型。保留完整微生物组的模型中明显的最大贡献（即避免使用抗生素）我们将根据这些观察结果来确定念珠菌溶素肽或其他 Ece1 肽也有助于共生适应性。我们的研究还将解决 Ece1 是否有助于共生适应性。影响细菌微生物组或宿主对白色念珠菌的反应，以及是否编码 Ece1 肽促进真菌易位到血液中，从而促进全身性疾病。此外，我们发现 ECE1 等位基因之间存在显着水平的序列多样性因此，我们将在不同的临床收集中定义 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。实验将有可能确定 ECE1 在确定菌株特异性差异方面的作用物种。这些研究将共同确定 ECE1（和念珠菌溶酶）对健康的贡献我们预计共生胃肠道生态位中白色念珠菌细胞的数量，以及宿主对这种真菌的反应。这些实验将扩大我们对导致白色念珠菌产生的真菌因素的理解定植，包括 Ece1 在这种重要病原体的生物学中的精确作用。