Host-Pathogen Interaction in Leptospirosis

钩端螺旋体病中宿主与病原体的相互作用

• 批准号: 10643286
• 负责人: DAVID A HAAKE
• 金额: $ 246.3万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643286
• 关键词: Acute; Adherens Junction; Animal Model; Animals; Antibiotics; Bacterial Adhesins; Basic Science; Biological Markers; Chronic; Clinical; Clinical Data; Collaborations; Creativeness; Critical Illness; Data; Development; Diagnostic; Disease; Disease Outcome; Disease susceptibility; Ecology; Endothelial Cells; Endothelium; Epidemiology; Etiology; Failure; Fever; Fostering; Genetic Transcription; Genome; Goals; Hamsters; Health; Human; Immune response; In Vitro; Infection; Inflammasome; Inflammatory Response Pathway; Innate Immune Response; Interdisciplinary Study; Interferon Type I; Interleukin-1 beta; International; Intervention; Invaded; Leptospira; Leptospira interrogans; Leptospirosis; Macrophage; Mission; Mus; Nicaragua; Occupational; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Phagocytes; Phenotype; Predisposition; Prognostic Marker; Public Health; Recreation; Research; Research Personnel; Resource-limited setting; Role; Rural; Sampling; Science; Severities; Severity of illness; Site; Small RNA; Sri Lanka; Structure; Study models; Tanzania; Testing; Translational Research; Translations; Triage; United States National Institutes of Health; Untranslated RNA; Validation; Virulence; Virulence Factors; Wisconsin; Work; adjudication; arm; biobank; cadherin 5; clinical research site; diagnostic biomarker; diagnostic tool; field study; follow-up; genetic manipulation; genome-wide; improved; in vitro testing; in vivo; inflammatory marker; innovation; insight; medical schools; monolayer; mortality; pathogen; predictive tools; prevent; prognostic tool; programs; prospective; response; tool; virulence gene

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.

摘要：整体组件 钩端螺旋体病是一种广泛且经常致命的人类健康问题， 资源设置。由于人们对钩端螺旋体病的宿主-病原体动力学研究知之甚少，因此具有重要意义 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 作为钩端螺旋体研究领导者的项目研究者之间的协同合作 毒力基因（Haake和Picardeau）、内皮相互作用（Coburn）、炎性体途径 （Sutterwala）和急性发热性疾病的实地研究（Reller和Woods）。随着许多新的描述 钩端螺旋体基因组，大量物种多样性的惊人模式已经出现，导致中心假设 #1，这是一组核心的钩端螺旋体毒力因子已经进化出在哺乳动物宿主中的生存作用 吞噬细胞，易位和传播，这是上调响应宿主微环境。 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 在宿主吞噬细胞内的存活和穿过内皮屏障的移位。炎症相关性 IL-1β水平与疾病严重程度的相关性导致中心假设#2，即人类 炎症反应途径驱动疾病结果。中心假设2将在体外进行检验 （与巨噬细胞和内皮细胞的相互作用），动物模型（仓鼠和小鼠感染），以及 在坦桑尼亚、尼加拉瓜和斯里兰卡的人类实地研究中。具体而言，我们将继续推进我们的创新 发现了人类巨噬细胞中高水平炎性小体活化与 以及来自小鼠的巨噬细胞中的低水平，这些巨噬细胞是储存宿主并且不表现出疾病。我们还将 继续我们的创新发现，即致病性血管生成因子对内皮细胞VE-钙粘蛋白的显著破坏， 钩端螺旋体在细胞间侵入传播中的作用。动物模型研究将提供 纵向宿主反应数据，以支持人类研究，这将产生积极的影响， 开发和验证快速生物标志物诊断和分诊工具，以确定严重感染， 早期阶段，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严重疾病 肝肾衰竭