Predicting Risk of Human Leptospiros by Environmental Surveillance

描述（由申请人提供）：钩端螺旋体病是世界上最重要的人畜共患传染病之一，每年影响全球约868,000人，估计病死率为5-10%。在将钩端螺旋体和钩端螺旋体病研究的最新基本分子进展转化为预防和改善这种传染病的公共卫生方法方面，仍存在重大差距。该项目的长期目标是开发和验证新的工具和方法，以减少钩端螺旋体病对人类健康的影响。这里提出的研究将检验中心假设，即通过使用宏基因组和深度测序工具，量化和识别环境地表水和土壤（人类感染的最重要来源）中的传染性钩端螺旋体（致病性和中间致病性物种和血清型），可以预测人类感染钩端螺旋体病的风险和感染的临床结果。这一假设将在三个具体目标中得到检验：1)在秘鲁伊基托斯市城乡地区进行前瞻性、观察性、基于人群的队列研究，确定急性钩端螺旋体病的发病率，以及钩端螺旋体肾携带的患病率、持续时间和临床后果；2)在秘鲁伊基托斯市钩端螺旋体流行的城市和农村社区，量化、识别和确定传染性钩端螺旋体在可能的环境传播源中的局部分布；3)确定发现钩端螺旋体的城市与农村环境背景，量化和分型是否可以预测人类感染严重钩端螺旋体病与非严重钩端螺旋体病的风险。利用最近开发的技术，将首次在秘鲁亚马逊地区流行病学环境对比的观察性、基于人群的前瞻性队列研究中研究高度地方性钩端螺旋体感染的自然历史和临床结果。慢性肾脏感染的病理生物学意义将通过尿液生物标志物来确定，这些生物标志物表明肾小管结构损伤。将利用宏基因组技术确定潜在环境传染源中钩端螺旋体的数量和种类/血清型。这一多学科项目将提供关键数据，以推动制定旨在减少钩端螺旋体病人类风险的公共卫生政策。研究结果将适用于全球其他受钩端螺旋体病影响的地区，并有可能推广到具有关键生态/流行病学背景的其他传染病，例如由肠道病原体引起的传染病。将首次在人口水平上精确确定高度流行环境中钩端螺旋体病的自然历史和临床影响，这是准确估计这一具有全球重要性的人畜共患疾病负担的重要数据。最终，该项目将验证环境监测是否可以作为确定和消除钩端螺旋体病传播源的公共卫生工具。

DESCRIPTION (provided by applicant): Leptospirosis is among the world's most important zoonotic infectious diseases, annually affecting an estimated 868,000 people globally, with an estimated case fatality rate of 5-10%. Important gaps remain in translating recent fundamental molecular advances in studies of Leptospira and leptospirosis4 to public health approaches to preventing and ameliorating this infectious disease. The long-term goal of this project is to develop and validate new tools and approaches to reduce the impact of leptospirosis on human health. The studies proposed here will test the central hypothesis that human risk for acquiring leptospirosis and clinical outcomes of infection can be predicted by quantifying and identifying infectious Leptospira (pathogenic and intermediately pathogenic species and serovars) in environmental surface waters and soils (most important sources of human infection) using metagenomic and deep sequencing tools. This hypothesis will be tested in three Specific Aims: 1) To determine the incidence of acute leptospirosis, and the prevalence, duration and clinical consequences of Leptospira renal carriage in prospective, observational, population- based cohort studies in urban and rural areas of Iquitos, Peru; 2) To quantify, identify and determine the local distribution of infectious Leptospira in likely environmental sources of transmission in leptospirosis-endemic urban and rural communities of Iquitos, Peru; and 3) To determine whether the urban vs. rural environmental contexts in which Leptospira are found, quantified and typed can predict risk for humans for acquiring severe vs. non-severe leptospirosis. Using recently developed techniques, the natural history and clinical outcomes of highly endemic leptospiral infection will be studied, for the first time, in observational, population-based, prospective cohort studies in contrasting epidemiological settings in the Peruvian Amazon. The patho-biological significance of chronic renal infection will be determined using urinary biomarkers that indicate renal tubular structural damage. The quantity and Leptospira species/serovars in potential environmental sources of transmission will be determined using metagenomic techniques. This multidisciplinary project will provide key data to drive the development of public health policies aimed at reducing the human risk of leptospirosis. The study results will be globally applicable to other regions affected by leptospirosis, and have the potential to be generalizable to other infectious diseases that have key eco/epidemiological contexts, such as those caused by enteric pathogens. For the first time, the natural history and clinical impact of leptospirosis in a highly endemic setting will be precisely determined at a population level, essential data for accurately estimating the burden of this globally-important zoonotic disease. Ultimately, this project will validate whether environmental surveillance can be deployed as a public health tool for identifying and eliminating sources of leptospirosis transmission.