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; 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.

项目摘要 钩端螺旋体病是一种新兴的传染病，是发病率和死亡率的主要人畜共患病 在全球范围内，对生存农民和城市贫民窟人群的负担最大。钩端螺旋体病会导致生命 - 威胁性疾病，并已成为全球肺出血综合征（LPH）的主要原因 和急性肾脏受伤。迄今为止，尚无有效的预防和控制资源贫乏的钩端螺旋体病 设置。在美国和其他工业化国家，钩端螺旋体病是市中心疾病的主要原因 人口，军事人员以及从事游泳和水运动的个人。钩端螺旋体病是由 在十七个致病性中属于300多种血清的环境传播的螺旋体 Leptospira属内的物种，该属还包括26种非致病物种和21种中间体 物种，后者具有不确定的疾病病因。钩端螺旋体感染的标志 它是在生物通过粘膜穿透后的快速血源传播，散布 到整个主机的多个器官。尽管与钩端螺旋体病有关的疾病负担很大，但 与钩端螺旋体相关的发病机理的生物学和遗传机制仍然鲜为人知。这 知识的关键差距损害了更好的诊断和控制工具的发展。在此探索性中 提案，我们假设基因表达的转移以及基因的分歧和收敛进化 功能，导致了钩端螺旋体的能力多样性，在宿主和兼职 致病性。为了识别负责致病性的基因，我们将使用比较系统生物学 在这种方法中，我们使用体外感染的体外感染模型在物种上介绍了转录 替代基因表达。那些在体外模型模仿细菌和细菌的流行病学生命周期 生物过程对于建立疾病必不可少。通过访问我们广泛的基于HIMAR1的图书馆 突变体，我们将确定其中一些靶标的基因破坏的菌株。通过已知的功能 使用依从性和易位的体外测定法和生存的能力 并在水和土壤等环境矩阵中壮成长，我们将确定并表征那些的作用 致病性和传播中的基因。获取有关致病性基因身份的知识 传播是分子理解钩端螺旋体发病机理的主要优先级 这将直接通过改进诊断的发展直接促进公共卫生措施的进步 和预防方法。