Predicting Risk of Human Leptospiros by Environmental Surveillance

描述（由申请方提供）：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4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，仍然存在重要差距。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。本文提出的研究将检验中心假设，即人类获得钩端螺旋体病的风险和感染的临床结果可以通过使用宏基因组和深度测序工具定量和鉴定环境表面沃茨和土壤（人类感染的最重要来源）中的传染性钩端螺旋体（致病性和中等致病性物种和血清型）来预测。将在三个特定目的中检验这一假设：1）在秘鲁伊基托斯的城市和农村地区进行前瞻性、观察性、基于人群的队列研究，以确定急性钩端螺旋体病的发病率以及肾携带钩端螺旋体的患病率、持续时间和临床后果; 2）量化，在钩端螺旋体病传播的可能环境来源中识别和确定传染性钩端螺旋体的局部分布-秘鲁伊基托斯的地方性城市和农村社区;和3）确定发现、量化和分型钩端螺旋体的城市与农村环境背景是否可以预测人类获得重度与非重度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对比流行病学背景的观察性、以人群为基础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史和临床结果。将使用指示肾小管结构损伤的尿液生物标志物来确定慢性肾脏感染的病理生物学意义。将使用宏基因组技术确定潜在环境传播源中的数量和钩端螺旋体种属/血清型。这一多学科项目将提供关键数据，推动制定旨在降低人类感染钩端螺旋体病风险的公共卫生政策。研究结果将在全球范围内适用于受钩端螺旋体病影响的其他地区，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，如由肠道病原体引起的传染病。这是第一次在人群水平上精确地确定钩端螺旋体病在高度流行环境中的自然史和临床影响，这是准确估计这种全球重要的人畜共患病负担的基本数据。最终，该项目将验证环境监测是否可以作为一种公共卫生工具，用于识别和消除钩端螺旋体病传播源。

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.