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：整体组成 钩端螺旋体病是一种广泛且经常致命的人类健康问题，对低血压造成不成比例的影响。 钩端螺旋体病宿主-病原体动态的研究非常重要，因为我们知之甚少。 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。 作为钩端螺旋体研究领导者的项目研究人员之间的协同合作 毒力基因（Haake 和 Picardeau）、内皮相互作用（Coburn）、炎症小体途径 （Sutterwala），以及急性发热性疾病的实地研究（Reller 和 Woods），其中有许多新的描述。 钩端螺旋体基因组，出现了大规模物种多样性的惊人模式，导致了中心假设 #1，一组核心的钩端螺旋体毒力因子已经进化，在哺乳动物宿主的生存中发挥作用 吞噬细胞、易位和传播，这些细胞响应宿主微环境而上调。 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关联起来进行检验 表型，检查转录调节因子和非编码小RNA在适应和 宿主吞噬细胞内的存活和跨内皮屏障的易位与炎症的相关性。 IL-1β 水平等标记物与疾病严重程度的关系引出了中心假设#2，即人类 炎症反应途径驱动疾病结果将在体外进行测试。 （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 具体来说，我们将在坦桑尼亚、尼加拉瓜和斯里兰卡开展人类实地研究。 发现人类巨噬细胞高水平炎症小体激活之间的惊人二分法 小鼠的巨噬细胞水平较低，它们是储存宿主，不会表现出疾病。 跟进我们的创新发现，即病原体对内皮 VE-钙粘蛋白的显着破坏 动物模型研究将提供钩端螺旋体在细胞间侵袭中的作用。 支持人类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志物诊断和分类工具，以识别严重感染 抗生素和其他干预措施可以预防和/或治疗危重疾病（包括致命疾病）的早期阶段 肝肾衰竭。