Mechanisms of Leptospira interrogans interactions with the vascular endothelium in vivo

问号钩端螺旋体与体内血管内皮相互作用的机制

基本信息

批准号：
10208696
负责人：
Jenifer L Coburn
金额：
$ 23.7万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-02 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208696
关键词：
Actins Acute Address Adherence Adherens Junction Adhesions Adhesives Affect Animals Bacteria Bacterial Adhesins Binding Blood Blood Vessels Borrelia Borrelia burgdorferi C3H/HeJ Mouse Cell Surface Receptors Cell surface Cells Chronic Clinical Collection Communicable Diseases Complement Complex Cytoskeleton Data Development Disease Dose Drug or chemical Tissue Distribution Endothelial Cells Endothelium Endotoxins Environment Exposure to Extracellular Matrix Female Genome Hemorrhage Human Impairment In Vitro Infection Intercellular Junctions Intravenous Invaded Kidney Failure Leptospira Leptospira interrogans Leptospirosis Life Lipopolysaccharides Liquid substance Liver Dysfunction Livestock Lung Maintenance Minor Modeling Mouse Strains Mucous Membrane Multiple Organ Failure Mus Mutation Order Spirochaetales Pathogenesis Pathogenicity Proteins Proximal Kidney Tubules Recombinants Role Severities Site Skin Slum Soil Source TLR4 gene Testing Time Tissues Treponema Urine Ursidae Family Vascular Endothelium Vascular Permeabilities Water Work Zoonoses burden of illness cadherin 5 companion animal gain of function in vivo insight male member mouse model mutant pathogen receptor

项目摘要

Abstract Leptospirosis is the most widespread zoonotic disease worldwide, and continues to emerge as a significant infectious disease in urban slums, particularly in tropical regions. Several species of the genus Leptospira can cause infection, which varies in severity from mild illness to fatal hemorrhagic disease with multiple organ failure. Typically, infection of a maintenance (reservoir) host is chronic and asymptomatic. Yet, the same bacterium can cause acute, potentially life-threatening infection in an accidental host species. Persistence of leptospires in wildlife, companion animals, and livestock provides a constant reservoir for human infection, as infected animals harbor Leptospira in the proximal tubules of the kidney and excrete Leptospira in the urine. Release of viable bacteria into the environment provides opportunities for infection of new hosts. Infection is acquired through exposure to animal bodily fluids, especially urine, or from environmental sources contaminated with urine. Entry is typically through mucous membranes or minor breaches in the skin, followed by dissemination to multiple sites. Widespread endothelial damage is a prominent feature of leptospirosis. Despite the global burden of disease, the pathogenic mechanisms of Leptospira species are understudied. Adhesion to host molecules is critical to the abilities of many pathogens to establish infection and cause disease, and is likely true for Leptospira, as well. Adhesion to host cell surface molecules may facilitate invasion of tissues, but to date this question has not been mechanistically addressed. While several candidate adhesive proteins have been identified, how these activities contribute to pathogenicity in vivo remains unknown. We demonstrated that the major contributor to endothelial cell-cell junctions, VE-cadherin, is a receptor for L. interrogans. We also identified two adhesins that bind to VE-cadherin, demonstrated that L. interrogans and purified recombinant adhesins cause disruption of adherens junctions, which are critical to maintenance of endothelial integrity. In our work on another spirochete, Borrelia burgdorferi, we developed a short-term intravenous inoculation model to determine the roles of B. burgdorferi proteins in interactions with the vasculature in different tissue sites in living mice. In this exploratory/developmental project, we will test the hypothesis that specific L. interrogans proteins contribute to bacterial interaction with the endothelium in vivo. In Aim 1 we will test the hypothesis that L. interrogans interacts with the vascular endothelium in living animals, and in Aim 2 we will test the hypothesis that specific L. interrogans proteins that adhere to VE-cadherin in vitro have roles in adherence of the bacteria to the endothelium in vivo. This exploratory/developmental work will refine the mechanism by which three L. interrogans adhesins contribute to the pathogenesis of leptospirosis.

抽象的钩端螺旋体病是全球最广泛的人畜共患病，并继续作为一种城市贫民窟的重要传染病，特别是在热带地区。几种钩端螺旋体可能引起感染，从而严重程度从轻度疾病到致命的出血具有多器官衰竭的疾病。通常，感染维护（水库）主机是慢性的，并且无症状。然而，同一细菌会引起急性，潜在地威胁生命的感染意外宿主物种。在野生动植物，伴侣动物和牲畜中的诱饵持续存在为人类感染提供了一个恒定的储层，因为感染的动物在近端有钩端螺旋体尿液中的肾脏和排泄钩端螺旋体的小管。释放可行的细菌环境为新宿主感染提供了机会。通过暴露获得感染动物体液，尤其是尿液，或者来自被尿液污染的环境源。条目是通常通过粘膜或皮肤中的轻微破坏，然后传播到多个站点。广泛的内皮损害是钩端螺旋体病的重要特征。尽管疾病的全球负担，但钩端螺旋体的致病机制是研究了。对宿主分子的粘附对于许多病原体的能力至关重要感染并引起疾病，并且对于钩端螺旋体也可能是正确的。对宿主细胞表面的粘附分子可能有助于侵袭组织，但迄今为止，这个问题尚未机械上解决。虽然已经确定了几种候选粘合剂蛋白，但这些活动如何体内有助于致病性仍然未知。我们证明了内皮细胞细胞连接蛋白的主要贡献者是一种受体对于L. erentogans。我们还确定了两种与VE-钙粘蛋白结合的粘附蛋白，证明了L. 介绍和纯化的重组粘附素会导致粘附连接的破坏，这是维持内皮完整性至关重要。在我们在另一个螺旋体的工作中我们开发了一种短期静脉接种模型，以确定B. burgdorferi的作用与活小鼠不同组织部位的脉管系统相互作用的蛋白质。在这个探索性/发展项目，我们将测试特定的L. discerogans蛋白的假设有助于与体内内皮的细菌相互作用。在AIM 1中，我们将检验以下假设 L.探究与活动物中血管内皮相互作用，在AIM 2中，我们将测试假设在体外粘附于Ve-钙粘蛋白的特定杂种蛋白在体外具有作用细菌遵守体内内皮。这项探索性/发展工作将完善三乳杆菌粘附素有助于钩端螺旋体病的发病机理的机制。