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.

Gallosolyticus亚种链球菌。 Gallolyticus（SGG）是导致医学上重要的肠道病原体 威胁生命的菌血症和感染性心内膜炎（IE）并促进结直肠癌（CRC）。但是， SGG致病性基础的分子机制仍然很少理解。 SGG的致病过程 （以前称为Bovis Biotype I）涉及结肠定位，影响结肠上皮 稳态和障碍完整性，并从肠道到循环系统传播以引起菌血症 即我们的长期目标是了解该生物如何定居结肠，如何影响肠道上皮 稳态和正直，以及如何利用知识来减轻SGG引起的病理。此应用程序 将研究一种新的机制，该机制介导SGG依从性上的上皮。 先前的研究表明，SGG对结肠上皮细胞的依从性促进了肠道定植24,25，并且 与其促进细胞增殖的能力13和易位23有关。因此，遵守结肠 上皮是SGG致病过程中的关键早期一步 了解SGG依从性是有限的。额外的依从性机制仍有旨在阐明以填充 主要的知识差距。 该提议的假设是SGG的两个VII分泌系统（T7SS）的两个组成部分 通过靶向特定的宿主细胞受体，协作介导SGG对结肠上皮的依从性。 T7SS是一种专门的分泌系统，已知可以介导与宿主的病原体相互作用。已经显示 对于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 SGG菌株TX20005（T7SST05）中T7SS的功能表征，并证明该T7SS是一个 SGG的致病性决定因素。特别是，删除T7SST05分泌机械的核心组件 导致粘附于结肠上皮细胞的能力显着降低，并在体内定居。 该提案的目标是定义T7SST05组件在遵守结肠中的作用 上皮（AIM 1），并确定SGG靶向的宿主细胞表面受体（AIM 2）。给出 对SGG致病性的机械理解有限，拟议的工作将提供至关重要的工作 在识别介导结肠上皮定植的新型分子玩家方面的突破， 从而填补了重大的知识差距。此外，这项工作中确定的特定SGG因素是候选人 用于诊断生物标志物和临床干预靶标，因此具有翻译潜力。