Disease Determinants of Urban Leptospirosis

描述（由申请人提供）：钩端螺旋体病是城市贫民窟健康问题的典范。世界范围内快速的城市化和不断扩大的城市贫困为螺旋体钩端螺旋体的鼠传传播创造了条件。康奈尔大学威尔医学院和巴西萨尔瓦多市奥斯瓦尔多克鲁兹基金会的调查提高了人们对钩体病新模式的认识，其特点是每年与降雨有关的流行病发生在贫民窟社区，并导致危及生命的症状，如肺出血综合征。缺乏充分的诊断和对疾病发病机制了解不足，是对城市流行病采取有效公共卫生对策的主要障碍。我们在萨尔瓦多建立了钩端螺旋体病的主动监测，并对城市贫民窟人口进行了长期前瞻性研究。这些研究对疾病传播中的病原体、环境和宿主相关因素提出了具体假设。我们提出了一个ICIDR项目，该项目将基因组学和蛋白质组学的最新方法应用于正在进行的实地调查，目的是阐明城市钩端螺旋体病的决定因素。在第一个项目目标中，我们将利用临床分离物的高通量基因组测序和遗传工具来操纵钩端螺旋体，确定影响肺出血综合征疾病进展和发展的病原体因素。在第二个项目目标中，我们将开发分子检测方法来测量环境中的钩端螺旋体，并确定这种检测方法是否可用于识别传播源、对疾病风险进行分层和在资源贫乏环境中优先预防。在第三个项目目标中，我们将使用蛋白质组阵列系统地识别钩端螺旋体病的诊断和预后标记物，以及潜在的候选疫苗。所获得的信息可能导致新的干预战略，例如有针对性的环境控制措施、改进的诊断和疫苗，这些都是迫切需要的，因为世界上居住在贫民窟的人口在未来20年内将从10亿增加到20亿。此外，该项目将在巴西建立转化研究能力，以解决其他被忽视的传染病问题。

DESCRIPTION (provided by applicant): Leptospirosis is a paradigm for an urban slum health problem. Rapid urbanization and expanding urban poverty worldwide have created conditions for rat-borne transmission of the Leptospira spirochete. The investigations of Weill Medical College of Cornell University and Oswaldo Cruz Foundation in the city of Salvador, Brazil raised awareness for a new pattern for leptospirosis, characterized by annual rainfall-associated epidemics that occur in slum communities and cause life-threatening manifestations such pulmonary hemorrhage syndrome. The lack of adequate diagnostics and poor understanding of disease pathogenesis are the major barriers to mounting effective public health responses to urban epidemics. We have established active surveillance for leptospirosis in Salvador and performed long-term prospective studies of urban slum populations. These studies raise specific hypotheses on the pathogen, environment and host-related factors in disease transmission. We propose an ICIDR project which applies state-of-the-art approaches in genomics and proteomics to ongoing field investigations for the aim of elucidating the determinants of urban leptospirosis. In the first project aim, we will identify the pathogen factors which influence disease progression and development of pulmonary hemorrhage syndrome using high-throughput genome sequencing of clinical isolates and genetic tools to manipulate Leptospira. In the second project aim, we will develop molecular assays to measure Leptospira in the environment and determine whether such assays can be used to identify transmission sources, stratify disease risk and prioritize prevention in resource-poor settings. In the third project aim, we will use proteome arrays to systematically identify diagnostic and prognostic markers for leptospirosis, as well as potential vaccine candidates. The information gained may lead to novel strategies for intervention, such as targeted environmental control measures, improved diagnostics and vaccines, which are urgently needed as the world's population residing in slums doubles from one to two billion in the next twenty years. Furthermore the ICIDR project will create the translational research capacity in Brazil to address other neglected infectious diseases. RELEVANCE: There is no effective prevention for leptospirosis, a life-threatening bacterial disease which causes epidemics among the urban poor worldwide. The proposed research will apply state-of-the art molecular approaches to field investigations in Brazil for the purpose of characterizing the disease determinants of leptospirosis and identifying novel strategies for intervention, such as improved diagnostics and vaccines.