Adhesion of Leptospira interrogans to the Renal Proximal Tubule

描述(申请人提供)：钩端螺旋体病是世界上传播最广泛的人畜共患病，在城市贫民窟，特别是在热带地区，正在成为一种严重的传染病。钩端螺旋体属的几个物种可以引起感染，其严重程度从轻微疾病到伴有多器官衰竭的致命出血性疾病不等。通常情况下，维持性(水库)宿主的感染是慢性和无症状的。几乎所有种类的哺乳动物都可以作为这种细菌的储存库，感染的幸存者在肾脏近端小管中携带钩端螺旋体，并从尿液中排泄钩端螺旋体。将活细菌释放到环境中为感染新宿主提供了机会。野生动物、伴生动物和家畜肾脏中的钩端螺旋体持续存在，为人类感染提供了持续的蓄水池。尽管钩端螺旋体对人类和动物造成了全球性的疾病负担，但钩端螺旋体物种用来促进定植、传播和疾病的机制尚未确定。虽然钩端螺旋体几乎可以传播到任何组织，但持续感染的流行病学关键部位是近端小管，螺旋体明显附着在上皮细胞的管腔方面。然而，目前尚不清楚致病钩端螺旋体物种如何与近端小管中的宿主细胞相互作用。我们的假设是，致病钩端螺旋体物种通过针对宿主细胞表面的特定黏附素附着到近端小管上皮细胞。我们已经证明，问号钩端螺旋体与细胞的结合比与细胞沉积的ECM更有效，并使用噬菌体展示技术，根据选择与内皮细胞结合的基础上鉴定了几种细胞特异性粘附素。为了填补在理解问号钩端螺旋体感染和致病机制方面的关键知识空白，我们将在我们的专业知识和试剂的基础上，选择能够介导与近端小管细胞相互作用的问号钩端螺旋体粘附素。然后，我们将评估与其他物种的近端小管细胞和宿主细胞受体结合的候选粘附素 我们已经确定，对于细菌表面的暴露，以及在钩端螺旋体感染期间细菌的表达。我们预计，这项工作将加快确定新的候选疫苗和治疗干预措施，以扰乱动物水库中致病钩端螺旋体物种的维持，从而降低人和动物感染的风险。

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.