Host-Pathogen Interaction in Leptospirosis

摘要：整体组件 钩端螺旋体病是一种广泛和经常致命的人类健康问题，对低收入人群的影响不成比例。 资源设置。钩端螺旋体病的宿主-病原体动力学研究具有重要意义，因为人们对此知之甚少 关于钩端螺旋体毒力因子或宿主对钩端螺旋体病的反应。拟议的研究将涉及高度 钩端螺旋体研究带头人的项目研究人员之间的协同合作 毒力基因(Haake和Picardeau)、内皮细胞相互作用(Coburn)、炎症体途径 (Sutterwala)，以及对急性发热病的实地研究(Reller和Wood)。描述了许多新的 钩端螺旋体基因组，一种巨大的物种多样性的显著模式已经出现，导致了中心假设 #1，这是一组核心的钩端螺旋体毒力因子已经进化，在哺乳动物宿主中扮演着生存的角色 吞噬细胞、移位和扩散，这些都是对宿主微环境的反应而上调的。 中心假设1将通过将基因组规模的钩端螺旋体进化变化与毒力相关联来检验 表型，研究转录调节因子和非编码小RNA在适应和 在宿主吞噬细胞内存活，并跨越内皮屏障。炎症性疾病的相关性 诸如IL-1β水平与疾病严重程度的标记物导致了中心假说2，即人类 炎症反应途径决定了疾病的结局。中心假说2将在体外进行测试 (与巨噬细胞和内皮细胞的相互作用)，在动物模型中(仓鼠和小鼠的感染)，以及 在坦桑尼亚、尼加拉瓜和斯里兰卡的人体田野研究中。具体地说，我们将跟进我们的创新 人巨噬细胞高水平炎性小体激活之间的显著二分 小鼠的巨噬细胞中的低水平，是宿主，不会表现出疾病。我们还将 继我们的创新发现内皮细胞VE-钙粘附素被致病基因戏剧性破坏 钩端螺旋体在细胞间入侵在传播中的作用。动物模型研究将提供 支持人体研究的纵向宿主反应数据将通过以下方式产生积极影响 开发和验证快速生物标记物诊断和分类工具，以识别严重感染 抗生素和其他干预措施可以预防和/或治疗包括致命疾病在内的危重疾病的早期阶段 肝肾功能衰竭。

Abstract: Overall Component Leptospirosis is a widespread and frequently fatal human health problem that disproportionately impacts low resource settings. Research on host-pathogen dynamics in leptospirosis are significant because little is known about leptospiral virulence factors or host response to leptospirosis. The proposed studies will involve highly synergistic collaborations between program project investigators who are leaders in studies of leptospiral virulence genes (Haake and Picardeau), endothelial interactions (Coburn), inflammasome pathways (Sutterwala), and field studies of acute febrile illness (Reller and Woods). With the description of many new leptospiral genomes, a striking pattern of massive species diversity has emerged leading to central hypothesis #1, which is that a core set of leptospiral virulence factors have evolved with roles in survival in mammalian host phagocytes, translocation, and dissemination, which are upregulated in response to the host microenvironment. Central hypothesis #1 will be tested by correlating genome-scale leptospiral evolutionary changes with virulence phenotypes, examining the roles of transcriptional regulators and non-coding small RNAs in adaptation to and survival within host phagocytes, and translocation across endothelial barriers. The correlation of inflammatory markers such as IL-1β levels with disease severity leads to central hypothesis #2, which is that human inflammatory response pathways drive disease outcomes. Central hypothesis #2 will be tested in vitro (interactions with macrophages and endothelial cells), in animal models (infections in hamsters and mice), and in human field studies in Tanzania, Nicaragua, and Sri Lanka. Specifically, we will follow up on our innovative discovery of a striking dichotomy between the high level of inflammasome activation in human macrophages and the low level in macrophages from mice, which are reservoir hosts and do not exhibit disease. We will also follow up on our innovative discovery of dramatic disruption of endothelial VE-cadherins by pathogenic leptospires in terms of the role of intercellular invasion in dissemination. Animal model studies will provide longitudinal host response data in support of human studies that will have a positive impact through development and validation of rapid biomarker diagnostic and triage tools to identify serious infections at an early stage when antibiotics and other interventions can prevent and/or treat critical illness including fatal hepatorenal failure.