Adhesion of Leptospira interrogans to the Renal Proximal Tubule

问号钩端螺旋体对肾近端小管的粘附

• 批准号: 8758246
• 负责人: Jenifer L Coburn
• 金额: $ 19.13万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8758246
• 关键词: Acute; Adhesions; Animals; Bacteria; Bacterial Adhesins; Binding; Biochemical; Cadherins; Cell Line; Cell Surface Receptors; Cell surface; Cells; Chronic; Communicable Diseases; Deposition; Detection; Disease; Endothelial Cells; Environment; Epidemiology; Epithelial; Epithelial Cells; Evaluation; Exposure to; Extracellular Matrix; Family suidae; Future; Genes; Genetic; Genomics; Goals; Hamsters; Health; Hematoxylin; Human; Immunohistochemistry; Infection; Kidney; Knowledge; Lead; Leptospira; Leptospira interrogans; Leptospirosis; Life; Liquid substance; Livestock; Maintenance; Mammals; Measures; Mediating; Minor; Molecular; Mucous Membrane; Multiple Organ Failure; New fuchsin; Order Spirochaetales; Orthologous Gene; Pathogenesis; Phage Display; Preventive; Protein Binding; Proteins; Proteoglycan; Proximal Kidney Tubules; Rattus; Reagent; Receptor Cell; Risk; Severities; Site; Skin; Slum; Soil; Source; Surface; Survivors; Therapeutic Intervention; Tissues; Tubular formation; Urine; Vaccines; Water; Work; base; burden of illness; cell type; companion animal; enzootic; genetic manipulation; genome sequencing; improved; insight; macromolecule; pathogen; public health relevance; receptor; tool; vaccine development

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.

描述（由申请人提供）：钩端螺旋体病是世界上传播最广的人畜共患疾病，正在成为城市贫民窟，特别是热带地区的一种重要传染病。钩端螺旋体属的几个物种可引起感染，其严重程度从轻微疾病到致命的多器官衰竭出血性疾病不等。通常，维持宿主（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宿主，感染的幸存者在肾脏的近端小管中携带钩端螺旋体，并通过尿液排出钩端螺旋体。将活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持续的宿主。尽管钩端螺旋体在人类和动物中造成全球疾病负担，但其促进定植、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，但流行病学上持续感染的关键部位是近端小管，其中螺旋体明显粘附在上皮细胞的管腔方面。然而，关于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通过靶向宿主细胞表面的特异性粘附素附着在近端小管上皮细胞上。我们已经证明，与细胞沉积的ECM相比，疑问乳杆菌与细胞的结合效率更高，并利用噬菌体展示技术，根据与内皮细胞结合的选择，鉴定了几种细胞特异性粘附素。为了填补了解乳杆菌感染和发病机制的关键知识空白，我们将利用我们的专业知识和试剂来选择乳杆菌粘附素，介导与近端小管细胞的相互作用。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