Cell-Binding Adhesins of Leptospira interrogans

描述(申请人提供)：在全球范围内，钩端螺旋体病是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，钩端螺旋体病也正在成为一种重要的传染病。这种感染是由钩端螺旋体属的螺旋体引起的，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。疾病的严重程度因寄主种类、寄主年龄和健康状况以及感染菌株而异。几乎所有种类的哺乳动物都可以作为携带者，钩端螺旋体持续存在于肾脏近端小管，并通过尿液排出。钩端螺旋体病在野生动物、伴生动物、牲畜，特别是牙周炎大鼠中持续存在，通过接触含有钩端螺旋体的动物组织或体液，或接触被尿液污染的水源，导致人类感染的持续宿主。细菌通过粘膜或皮肤擦伤进入，然后传播到多个组织，并可在特定部位建立持续感染，最重要的是肾脏近端小管。此外，广泛的内皮损伤是钩端螺旋体病的一个特征。黏附于宿主细胞表面和细胞外基质(ECM)是许多病原体致病的关键。钩端螺旋体可能也是如此，但以前对钩端螺旋体与哺乳动物组织成分的粘附性的研究主要集中在与细胞外基质的相互作用上。这项建议将继续我们最近的发现，即细菌与细胞表面的结合比与细胞外基质的结合更有效，并与内皮细胞的附着更有效 触发细胞层完整性的破坏，但不会杀死细胞。这些结果表明，致病钩端螺旋体与宿主的相互作用存在着额外的、重要的、未被探索的方面。该项目的目标是使用几种互补的方法来鉴定问号钩端螺旋体的分子，这些分子特别涉及与人类细胞表面受体的附着和改变宿主细胞的生物学。这项工作的长期目标是更好地了解钩端螺旋体与哺乳动物细胞相互作用的性质和后果，这最终可能有助于未来改进疫苗或治疗方法的开发。

DESCRIPTION (provided by applicant): On a worldwide basis, leptospirosis is the most widespread zoonotic disease. Leptospirosis is also emerging as a significant infectious disease in urban slums, particularly in tropical regions. The infection is caused by spirochetes of the genus Leptospira, and varies in severity from mild illness to fatal hemorrhagic disease with multiple organ failure. Disease severity varies with the host species, host age and health status, and the infecting strain. Virtually all species of mammals can serve as carriers, with the Leptospira persisting in the proximal tubules of the kidney and being shed in the urine. The persistence of leptospirosis in wildlife, companion animals, livestock, and in particular peridomestic rats, results in a continuous reservoir for human infection through exposure to animal tissue or body fluids containing Leptospira, or to urine-contaminated water sources. The bacteria enter through mucous membranes or skin abrasions, then disseminate to multiple tissues and can establish persistent infection in particular sites, most importantly the proximal tubules of the kidney. In addition, widespread endothelial damage is a feature of leptospirosis. Adhesion to host cell surfaces and extracellular matrix (ECM) is critical to the pathogenesis of disease for many pathogens. This is likely to be true of Leptospira, as well, but previous investigations into adhesion of Leptospira to mammalian tissue components have focused on interactions with the ECM. This proposal will follow up on our recent findings that the bacteria bind more efficiently to the cell surface than to the ECM, and that attachment to endothelial cells triggers disruption of cell layer integrity but does not kill the cells. These results suggest the presence of additional, significant, unexplored aspects of the interactions of pathogenic leptospires with the host. The goal of this project is to employ several complementary approaches to identify Leptospira interrogans molecules involved specifically in attachment to human cell surface receptors and altering the biology of host cells. The long-term goal of this line of work is to better understand the nature and consequences of Leptospira interactions with mammalian cells, which may eventually be useful in future development of improved vaccines or therapeutic approaches.