Cholera persistence, transmission, and clinical illness in Haiti

项目摘要/摘要 霍乱是一种古老的疾病，在现代世界显示出惊人的持续和传播能力， 据估计，全世界每年的疾病负担为130万至400万例。霍乱袭击海地 2010年10月，在当年1月12日大地震的余波中。这是第一批 海地100多年来报告的霍乱病例；早期病例分离株的克隆性质是一致的 通过单一来源的微生物介绍。共有754,735例霍乱病例和9,068人死亡 海地现已报告有霍乱病例，包括2015年的3万多例霍乱病例，反映出正在进行的大量 他强调了与疾病控制有关的问题，并强调需要继续进行霍乱基础研究和应用研究。 海地的霍乱代表了一种新的自然实验，涉及在一个单一的岛屿上引入 产毒霍乱弧菌O1的克隆，在已知时间点。因此，它提供了一个独特的机会 解决有关疾病的关键问题，并对我们了解和控制霍乱的能力产生影响 全球(与非洲部分地区特别相关，这些地区可能更像海地，而不是孟加拉国 或传统上进行霍乱研究的印度)。以我们现有的海地研究为基础 关于基础设施，我们建议探讨一系列问题：a)人与人之间的相对贡献是什么？ 人与环境之间的传播到海地霍乱的发生？B)司机是做什么的？ 霍乱患者中的症状感染？C)随着时间的推移，环境水库是否会持续存在？和d) 观察到的O1霍乱弧菌种群进化变化的驱动因素是什么？特定的 解决这些问题的目标和相关的工作假设如下： 具体目标1：利用家庭研究探索霍乱传播途径、无症状率 疾病，以及临床疾病的驱动因素。工作假设：a)在海地，从环境到人类的路线 传播引起的霍乱感染比人与人之间的传播更多；以及b) 症状性疾病的发生至少部分与肠道细菌的特定模式有关 微生物区系，和/或ICP2缺失/减少，可能还有其他溶血性霍乱噬菌体。 具体目标2：监测O1霍乱弧菌的水环境水库。工作假设：a) O1霍乱弧菌的水环境水库将在海地至少在未来5年内持续存在；和b) 缺乏对人类毒力至关重要的基因的O1霍乱弧菌环境分离频率将增加 随着环境水库随着时间的推移而“老化”。 具体目标3：霍乱弧菌O1菌株的系统动力学分析。工作假设：a)环境 分离株代表微生物的独立的、长期的储存群，表现出较慢的增长速度 进化和缓慢但显著的人口增长，以及b)临床和环境压力 种群经历正向选择，选择是由霍乱特异性噬菌体的存在驱动的。

Project Summary / Abstract Cholera, an ancient disease, has shown a remarkable ability to persist and spread in the modern world, with an estimated disease burden of 1.3 to 4.0 million cases per year worldwide. Cholera struck Haiti in October, 2010, in the aftermath of the massive earthquake on January 12 of that year. These were the first cholera cases reported in Haiti in over 100 years; the clonal nature of isolates from early cases is consistent with a single-source introduction of the microorganism. A total of 754,735 cholera cases and 9,068 deaths have now been reported in Haiti, including over 30,000 cholera cases in 2015, reflecting significant ongoing issues with disease control, and underscoring the need for continued basic and applied cholera research. Cholera in Haiti represents a novel natural experiment, involving introduction on an island of a single clone of toxigenic Vibrio cholerae O1, at a known point in time. As such, it provides a unique opportunity to address key questions about the disease, with implications for our ability to understand and control cholera globally (with particular relevance for parts of Africa, which may more closely resemble Haiti than Bangladesh or India, where cholera studies have traditionally been conducted). Building on our existing Haitian research infrastructure, we propose to explore a series of questions: a) What are the relative contributions of human-to- human vs. environment-to-human transmission to occurrence of cholera in Haiti? b) What are the drivers for symptomatic infection among cholera patients? c) Will environmental reservoirs persist over time? and d) What are the drivers for observed evolutionary changes within V. cholerae O1 strain populations? Specific Aims to address these questions, with associated working hypotheses, are as follows: Specific Aim 1: Use of household studies to explore routes of cholera transmission, rates of asymptomatic illness, and drivers for clinical illness. Working hypotheses: a) In Haiti, environmental-to-human routes of transmission are responsible for more cholera infections than human-to-human transmission; and b) Occurrence of symptomatic illness is associated, at least in part, with specific patterns of intestinal bacterial microflora, and/or absence/reduced numbers of ICP2 and, possibly, other lytic cholera bacteriophage. Specific Aim 2: Monitoring of aquatic environmental reservoirs for V. cholerae O1. Working hypotheses: a) Aquatic environmental reservoirs for V. cholerae O1 will persist in Haiti for at least the next 5 years; and b) Frequency of environmental isolation of V. cholerae O1 lacking genes critical for human virulence will increase as environmental reservoirs “age” across time. Specific Aim 3: Phylodynamic analysis of V. cholerae O1 strains. Working hypotheses: a) Environmental isolates represent independent, long-term reservoir populations of the microorganism, displaying a slower rate of evolution and a slower, albeit significant, population growth, and b) Both clinical and environmental strain populations undergo positive selection, with selection driven by presence of cholera-specific bacteriophage.