Type VII secretion in Streptococcus gallolyticus adherence

溶没食子链球菌粘附中的 VII 型分泌

• 批准号: 10593764
• 负责人: YI XU
• 金额: $ 18.36万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-14 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593764
• 关键词: Address; Adherence; Affect; Affinity; Antibodies; Area; Bacteremia; Cardiovascular system; Cell Proliferation; Cell Surface Receptors; Cells; Clinical; Colon; Colorectal Cancer; Data; Dependence; Development; Endocarditis; Engineering; Epidermal Growth Factor Receptor; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Future; Genetic; Goals; Growth Factor Receptors; Homeostasis; In Vitro; Individual; Infective endocarditis; Intervention; Knock-out; Knowledge; Life; Ligands; Light; Link; Malignant Neoplasms; Mediating; Medical; Modeling; Molecular; Organism; Pathogenesis; Pathogenicity; Pathology; Phenotype; Play; Process; Protein Secretion; Proteins; Publishing; Receptor Cell; Recombinant Proteins; Regulation; Reporting; Research; Role; Streptococcus; Streptococcus bovis; Surface; System; Testing; Time; Variant; Virulence; Work; biotypes; diagnostic biomarker; gastrointestinal epithelium; gut colonization; human pathogen; in vivo; innovation; knock-down; microbial; novel; pathobiont; pathogen; prevent; receptor; tool; translational potential

Streptococcus gallolyticus subsp. gallolyticus (Sgg) is a medically important gut pathobiont that causes life-threatening bacteremia and infective endocarditis (IE) and promotes colorectal cancer (CRC). However, the molecular mechanisms underlying Sgg pathogenicity remain poorly understood. The pathogenic process of Sgg (previously known as S. bovis biotype I) involves colonizing the colon, influencing the colonic epithelium homeostasis and barrier integrity, and disseminating from the gut to the circulatory system to cause bacteremia and IE. Our long-term goals are to understand how this organism colonizes the colon, how it affects gut epithelial homeostasis and integrity, and how to use the knowledge to mitigate Sgg-induced pathologies. This application will investigate a novel mechanism that mediates Sgg adherence to the colonic epithelium. Previous studies suggest that Sgg adherence to colonic epithelial cells facilitates gut colonization24,25, and is linked to its ability to promote cell proliferation13 and to translocate23. Thus, adherence to the colonic epithelium is a critical early step in the pathogenic process of Sgg, however, the current mechanistic understanding of Sgg adherence is limited. Additional adherence mechanisms remain to be elucidated to fill a major knowledge gap. The hypothesis of this proposal is that two components of a type VII secretion system (T7SS) of Sgg collaboratively mediate the adherence of Sgg to the colonic epithelium by targeting a specific host cell receptor. T7SS is a specialized secretion system known to mediate pathogen interactions with the host. It has been shown to be important for the virulence and persistence of other pathogens. The Xu lab recently reported the first functional characterization of a T7SS in Sgg strain TX20005 (T7SST05) and demonstrated that this T7SS is a pathogenicity determinant of Sgg. In particular, deletion of core components of the T7SST05 secretion machinery resulted in significantly reduced capacity to adhere to colonic epithelial cells and to colonize the colon in vivo. The objectives of this proposal are to define the role of the T7SST05 components in adherence to the colonic epithelium (Aim 1) and to determine the host cell surface receptor targeted by Sgg for adherence (Aim 2). Given the limited mechanistic understanding of Sgg pathogenicity, the proposed work will provide crucial breakthroughs in identifying novel molecular players that mediate Sgg colonization of the colonic epithelium, thereby fill a major knowledge gap. Furthermore, the specific Sgg factors identified in this work are candidates for diagnostic biomarkers and clinical intervention targets, and therefore have translational potential.

解没食子链球菌解没食子酸杆菌（Sgg）是一种医学上重要的肠道致病菌， 危及生命的菌血症和感染性心内膜炎（IE），并促进结直肠癌（CRC）。但 SGG致病性的分子机制仍然知之甚少。Sgg的致病过程 （以前称为S。牛生物型I）涉及结肠定植，影响结肠上皮 体内平衡和屏障完整性，并从肠道传播到循环系统引起菌血症 和IE。我们的长期目标是了解这种微生物是如何在结肠定植的，它如何影响肠道上皮细胞， 稳态和完整性，以及如何使用知识来减轻Sgg诱导的病理。本申请 将研究一种新的机制，介导SGG粘附到结肠上皮。 以前的研究表明，SGG粘附结肠上皮细胞促进肠道定植24，25， 与其促进细胞增殖13和易位23的能力有关。因此，粘附到结肠 上皮细胞是Sgg致病过程中的关键早期步骤，然而，目前的机制 对SGG依从性的理解是有限的。其他的粘附机制仍有待阐明，以填补 重大知识缺口。 该建议的假设是，Sgg的VII型分泌系统（T7SS）的两个组分 通过靶向特异性宿主细胞受体，协同介导Sgg粘附至结肠上皮。 T7SS是已知介导病原体与宿主相互作用的特化分泌系统。已经表明 对其他病原体的毒力和持久性很重要。徐实验室最近报道了第一个 在Sgg菌株TX20005（T7SST 05）中的T7SS的功能表征，并证明该T7SS是一种 Sgg致病性决定因子特别地，T7SST 05分泌机制的核心组分的缺失 导致粘附于结肠上皮细胞和在体内定殖结肠的能力显著降低。 本提案的目的是定义T7SST 05组件在结肠粘附中的作用。 上皮细胞（目的1）和确定宿主细胞表面受体的SGG针对粘附（目的2）。给定 有限的机制了解SGG致病性，拟议的工作将提供关键的 在鉴定介导SGG结肠上皮定殖的新分子方面的突破， 从而填补了一个重大的知识空白。此外，在这项工作中确定的特定Sgg因子是候选因子。 用于诊断生物标志物和临床干预靶点，因此具有转化潜力。