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 钩端螺旋体病是一个普遍且经常致命的人类健康问题，对低影响不成比例 资源设置。钩端螺旋体病中宿主病原体动力学的研究很重要，因为知之甚少 关于钩端螺旋体病毒因素或宿主对钩端螺旋体病的反应。拟议的研究将高度涉及 计划项目调查人员之间的协同合作，他们是瘦灵性研究的领导者 病毒基因（Haake和picardeau），内皮相互作用（Coburn），炎症途径 （Sutterwala）和急性高热疾病（Reller and Woods）的现场研究。描述了许多新的 钩端螺旋体基因组是大规模物种多样性的惊人模式，导致了中央假设 ＃1，这是一组钩端螺旋体病毒因子在哺乳动物宿主中的生存中演变 吞噬细胞，易位和传播，这些响应于宿主微环境。 中央假设＃1将通过将基因组规模的钩端螺旋进化变化与病毒相关联测试 表型，检查转录调节剂和非编码小RNA在适应和 宿主的吞噬细胞内的生存，以及跨内皮屏障的易位。炎症的相关性 诸如具有疾病严重程度的IL-1β水平等标记导致中心假设2，即人 炎症反应途径驱动疾病结果。中央假设2将在体外测试 （与巨噬细胞和内皮细胞相互作用），动物模型（仓鼠和小鼠的感染）和 在坦桑尼亚，尼加拉瓜和斯里兰卡的人类现场研究中。具体来说，我们将跟进我们的创新 在人类巨噬细胞中高水平的炎性体激活之间发现了惊人的二分法 以及小鼠巨噬细胞的低水平，这些小鼠是储层宿主，不表现出疾病。我们也会 跟进我们通过致病性对内皮VE-钙蛋白戏剧性破坏的创新发现 在细胞间入侵在传播中的作用方面的诱饵。动物模型研究将提供 纵向宿主响应数据支持人类研究，这将通过 快速生物标志物诊断和分类工具的开发和验证，以识别严重的感染 早期抗生素和其他干预措施可以预防和/或治疗包括致命的重症疾病 肝衰竭。