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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.

摘要