Cell-Binding Adhesins of Leptospira interrogans

描述（由申请人提供）：在世界范围内，钩端螺旋体病是传播最广的人畜共患疾病。钩端螺旋体病也正在成为城市贫民窟的一种重要传染病，特别是在热带地区。这种感染是由钩端螺旋体属的螺旋体引起的，其严重程度从轻微到多器官衰竭的致命出血性疾病不等。疾病严重程度随寄主种类、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的近端小管中，并随尿液排出。钩端螺旋体病在野生动物、伴侣动物、牲畜，特别是家养大鼠中的持续存在，通过暴露于含有钩端螺旋体的动物组织或体液，或暴露于尿液污染的水源，导致人类成为持续感染的宿主。细菌通过粘膜或皮肤擦伤进入，然后扩散到多个组织，并可在特定部位（最重要的是肾近端小管）建立持续感染。此外，广泛的内皮损伤是钩端螺旋体病的一个特征。对许多病原体来说，与宿主细胞表面和细胞外基质（ECM）的粘附是疾病发病的关键。钩端螺旋体可能也是如此，但之前对钩端螺旋体与哺乳动物组织成分粘附的研究主要集中在与ECM的相互作用上。这一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ECM的结合更有效，并且附着在内皮细胞上

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. PUBLIC HEALTH RELEVANCE: Leptospirosis is a potentially fatal infectious disease with global distribution. The higher prevalence of leptospirosis in the developing world suggests that preventive measures, such as vaccines that are effective against diverse Leptospira strains, would have a significant impact on human and animal health. As a step toward development of improved vaccines, we will identify and establish the significance of leptospiral molecules required for the bacteria to cause infection and disease manifestations.