Type VII secretion in Streptococcus gallolyticus adherence

溶没食子链球菌粘附中的 VII 型分泌

基本信息

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
项目类别：
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

项目摘要

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.

溶没食子链球菌亚种。溶没食子酸杆菌 (Sgg) 是一种医学上重要的肠道病原体，可导致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）。然而， Sgg 致病性的分子机制仍知之甚少。 Sgg的发病过程（以前称为牛链球菌生物型 I）涉及在结肠定殖，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导致菌血症和IE。我们的长期目标是了解这种生物体如何在结肠中定殖，如何影响肠道上皮细胞稳态和完整性，以及如何利用这些知识来减轻 Sgg 引起的病理。这个应用程序将研究一种介导 Sgg 粘附到结肠上皮的新机制。先前的研究表明，Sgg 粘附在结肠上皮细胞上有利于肠道定植24,25 和与其促进细胞增殖13 和易位23 的能力有关。因此，坚持结肠上皮细胞是 Sgg 致病过程中关键的早期步骤，然而，目前的机制对 Sgg 依从性的了解是有限的。额外的依从机制仍有待阐明，以填补主要知识差距。该提议的假设是 Sgg VII 型分泌系统（T7SS）的两个组成部分通过靶向特定的宿主细胞受体，协同介导 Sgg 与结肠上皮的粘附。 T7SS 是一种专门的分泌系统，已知可介导病原体与宿主的相互作用。已经显示了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对 Sgg 菌株 TX20005 (T7SST05) 中的 T7SS 进行功能表征，并证明该 T7SS 是 Sgg 的致病性决定因素。特别是 T7SST05 分泌机制核心组件的删除导致体内粘附结肠上皮细胞和定植结肠的能力显着降低。该提案的目标是定义 T7SST05 组件在遵守结肠规则方面的作用上皮细胞（目标 1）并确定 Sgg 粘附的宿主细胞表面受体（目标 2）。给定由于对 Sgg 致病性的机制了解有限，拟议的工作将提供至关重要的在鉴定介导 Sgg 结肠上皮定植的新型分子参与者方面取得了突破，从而填补了一个重大的知识空白。此外，本工作中确定的具体 Sgg 因素是候选因素用于诊断生物标志物和临床干预目标，因此具有转化潜力。