Evolutionary multispecies transcriptomics to reveal genes conferring pathogenicity within Leptospira spp

进化多物种转录组学揭示钩端螺旋体致病性基因

• 批准号: 10283483
• 负责人: Jeffrey Peter Townsend
• 金额: $ 25.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-09 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283483
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adherence; Adhesions; Affect; Animals; Awareness; Bacteria; Bayesian Network; Biological; Biological Assay; Biological Process; Biology; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Complex; Country; Destinations; Developed Countries; Development; Diagnostic; Disasters; Disease; Disease Outbreaks; Early Diagnosis; Emerging Communicable Diseases; Environment; Epidemiology; Essential Genes; Event; Evolution; Fresh Water; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Grant; Health; Hematogenous; Hemorrhage; Human; Hurricane; Impairment; In Vitro; Individual; Infection; Investigation; Knowledge; Leptospira; Leptospirosis; Libraries; Life; Life Cycle Stages; Lung; Measures; Methods; Military Personnel; Molecular; Morbidity - disease rate; Mucous Membrane; Natural History; Order Spirochaetales; Organ; Organism; Pathogenesis; Pathogenicity; Phenotype; Phylogenetic Analysis; Population; Prevention; Prevention approach; Process; Proteins; Public Health; Puerto Rico; Resources; Role; Slum; Soil; Source; Sports; Swimming; Syndrome; System; Testing; United States National Institutes of Health; Virulence; Water; Zoonoses; adhesion process; base; biological adaptation to stress; biological systems; burden of illness; candidate identification; comparative; design; differential expression; disorder prevention; farmer; gene function; gene interaction; genome-wide; improved; in vitro Assay; in vitro Model; in vivo; inner city; innovation; insight; mortality; mutant; neglect; pathogen; response; tool; transcriptomics; transmission process; vaccine development

PROJECT SUMMARY Leptospirosis is an emerging infectious disease and the leading zoonotic cause of morbidity and mortality worldwide, with its greatest burden on subsistence farmers and urban slum populations. Leptospirosis causes life- threatening disease and has emerged as a major cause worldwide of pulmonary hemorrhage syndrome (LPHS) and acute kidney injury. To date, there is no effective prevention and control for leptospirosis in resource-poor settings. In the US and other industrialized countries, leptospirosis is a major cause of disease among inner-city populations, military personnel, and individuals engaged in swimming and water sports. Leptospirosis is caused by environmentally transmitted spirochetes belonging to more than 300 serovars among seventeen pathogenic species within the genus Leptospira, a genus that also comprises 26 non-pathogenic species and 21 intermediate species, the latter with undefined role as disease causative agent. The hallmark of infection with Leptospira species is its rapid hematogenous dissemination after the organism penetrates through mucous membranes, disseminating to multiple organs throughout the host. Despite the sizable burden of disease associated with leptospirosis, the biological and genetic mechanisms of pathogenesis associated with Leptospira remain poorly understood. This crucial gap of knowledge has impaired the development of better diagnostic and control tools. In this exploratory proposal, we hypothesize that shifts in gene expression, together with divergent and convergent evolution of gene function, have led to diversity in ability of Leptospira to survive and thrive outside of the host and facultative pathogenicity. To identify genes responsible for pathogenicity, we will use a comparative systems biological approach, in which we profile transcription across species using in vitro models of infection that are in vivo surrogates for gene expression. Those in vitro models mimic the epidemiological life cycle of the bacteria and the biological processes essential to establish disease. Through access to our extensive library of himar1-based mutants, we will identify strains with gene disruption for some of those targets. Through known functional phenotypes using well-characterized in vitro assays of adherence and translocation, as well as ability to survive and thrive in environmental matrices such as water and soil, we will determine and characterize the role of those genes in pathogenicity and transmission. Acquiring knowledge of the identity of genes responsible for pathogenicity and transmission is a major priority for the molecular understanding of the mechanisms of leptospiral pathogenesis that will directly facilitate the advance of public health measures through the development of improved diagnostic and prevention methods.

项目概要 钩端螺旋体病是一种新出现的传染病，也是发病率和死亡率的主要原因人畜共患疾病 在世界范围内，自给自足的农民和城市贫民窟人口的负担最大。钩端螺旋体病导致生命—— 威胁性疾病，已成为全球肺出血综合征 (LPHS) 的主要原因 和急性肾损伤。迄今为止，资源匮乏地区钩端螺旋体病尚无有效的预防和控制方法 设置。在美国和其他工业化国家，钩端螺旋体病是市中心地区疾病的主要原因 人口、军事人员以及从事游泳和水上运动的个人。钩端螺旋体病是由 环境传播的螺旋体属于 17 种致病菌中的 300 多个血清型 钩端螺旋体属内的物种，该属还包括 26 种非致病性物种和 21 种中间物种 种，后者作为疾病病原体的作用不明确。钩端螺旋体感染的标志 是指微生物穿透粘膜后迅速经血行传播， 遍及宿主的多个器官。尽管与钩端螺旋体病相关的疾病负担相当大， 与钩端螺旋体相关的发病机制的生物学和遗传机制仍然知之甚少。这 严重的知识差距阻碍了更好的诊断和控制工具的开发。在这个探索性的 提议，我们假设基因表达的变化，以及基因的发散和趋同进化 功能，导致钩端螺旋体在宿主和兼性之外生存和繁衍的能力的多样性 致病性。为了识别负责致病性的基因，我们将使用生物比较系统 方法，其中我们使用体内感染的体外模型来分析跨物种的转录 基因表达的替代物。这些体外模型模拟了细菌的流行病学生命周期和 疾病发生所必需的生物过程。通过访问我们基于 himar1 的丰富库 突变体，我们将鉴定其中一些目标基因被破坏的菌株。通过已知的函数 使用充分表征的体外粘附和易位分析以及生存能力来确定表型 并在水和土壤等环境基质中茁壮成长，我们将确定和描述这些因素的作用 致病性和传播的基因。获得有关致病性基因身份的知识 传播是从分子角度理解钩端螺旋体发病机制的一个主要优先事项 这将通过开发改进的诊断技术直接促进公共卫生措施的进展 及预防方法。