Adhesion of Leptospira interrogans to the Renal Proximal Tubule

描述（由申请人提供）：钩端螺旋体病是世界范围内最广泛的人畜共患疾病，在城市贫民窟，特别是在热带地区，正在成为一种重要的传染病。钩端螺旋体属的几个物种可以引起感染，其严重程度从轻度疾病到致命的出血性疾病伴多器官衰竭不等。典型地，维持（储库）宿主的感染是慢性的且无症状的。几乎所有哺乳动物物种都可以成为细菌的宿主，感染的幸存者在肾脏近端小管中携带钩端螺旋体，并将钩端螺旋体排出尿液。活细菌释放到环境中为新宿主的感染提供了机会。钩端螺旋体在野生动物、伴侣动物和牲畜肾脏中的持续存在为人类感染提供了一个恒定的宿主。尽管人类和动物的疾病负担是全球性的，但钩端螺旋体物种促进定植、传播和疾病的机制尚未确定。虽然钩端螺旋体可以传播到几乎任何组织，但持续感染的流行病学关键部位是近端小管，其中螺旋体明显粘附于上皮细胞的腔面。然而，致病性钩端螺旋体物种如何与近端小管中的宿主细胞相互作用尚不清楚。我们的假设是，致病性钩端螺旋体物种附着到近端小管上皮细胞使用特定的粘附素靶向宿主细胞表面。我们证明了L.问号结合细胞比细胞沉积的ECM更有效，并且使用噬菌体展示，基于结合内皮细胞的选择鉴定了几种细胞特异性粘附素。填补了理解L的关键知识空白。问号线虫的感染和致病机制，我们将建立在我们的专业知识和试剂，以选择L。介导与近端小管细胞相互作用的问号状体粘附素。然后，我们将评估候选粘附素与其他物种的近端小管细胞和宿主细胞受体的结合， 我们已经确定，表面暴露在细菌上，并在钩端螺旋体病感染期间由细菌表达。我们预计，这项工作将加快确定新的候选人的疫苗和治疗干预措施，将破坏动物水库中的致病性钩端螺旋体物种的维护，从而降低人类和动物感染的风险。

DESCRIPTION (provided by applicant): Leptospirosis is the most widespread zoonotic disease worldwide, and is emerging as a significant infectious disease in urban slums, particularly in tropical regions. Several species of the genus Leptospira can cause infection, which can vary in severity from mild illness to fatal hemorrhagic disease with multiple organ failure. Typically, infection of a maintenance (reservoir) host is chronic and asymptomatic. Virtually all species of mammal can serve as reservoirs of the bacteria, with the survivors of infection harboring Leptospira in the proximal tubules of the kidney and excreting Leptospira in the urine. Release of viable bacteria into the environment provides opportunities for infection of new hosts. The persistence of leptospires in the kidneys of wildlife, companion animals, and livestock provides a constant reservoir for human infection. Despite the global burden of disease in humans and animals, the mechanisms used by Leptospira species to promote colonization, dissemination, and disease are not yet defined. While Leptospira species can disseminate to virtually any tissue, the epidemiologically critical site of persistent infection is the proximal tubules, in which spirochetes are clearly adherent to the luminal aspect of the epithelial cells. However, nothing is known about how pathogenic Leptospira species interact with host cells in the proximal tubules. Our hypothesis is that pathogenic Leptospira species attach to proximal tubule epithelial cells using specific adhesins targeting the host cell surface. We have demonstrated that L. interrogans binds to cells more efficiently than to the ECM deposited by the cells, and using phage display, identified several cell-specific adhesins based on selection for binding to endothelial cells. To fill a critical knowledge gap in understanding L. interrogans infection and pathogenesis, we will build on our expertise and reagents to select L. interrogans adhesins that mediate interactions with proximal tubule cells. We will then assess the candidate adhesins for binding to proximal tubule cells of additional species and to host cell receptors that that we have identified, for surface exposure on the bacteria, and for expression by the bacteria during leptospirosis infection. We anticipate that this work will expedite the identification of ne candidates for development of vaccines and therapeutic interventions that will disrupt the maintenance of pathogenic Leptospira species in animal reservoirs, thereby reducing risk of human and animal infections.