Cholera persistence, transmission, and clinical illness in Haiti

项目总结/摘要 霍乱是一种古老的疾病，它在现代世界表现出了非凡的持续和传播能力， 估计全世界每年有130万至400万病例。年霍乱袭击海地 2010年10月，在当年1月12日大地震之后。这就是最早的 海地100多年来报告的霍乱病例;早期病例的分离株的克隆性质是一致的 通过微生物的单一来源引入。共发生754 735例霍乱病例，9 068人死亡 包括2015年超过30，000例霍乱病例，反映了海地正在发生的重大疫情。 他强调，需要继续开展霍乱的基础和应用研究。 海地的霍乱代表了一种新颖的自然实验，涉及在一个岛上引入一种单一的 在已知时间点的致突变霍乱弧菌O 1的克隆。因此，它提供了一个独特的机会， 解决有关该疾病的关键问题，对我们理解和控制霍乱的能力产生影响 在全球范围内（特别是非洲部分地区，与孟加拉国相比， 或印度，那里传统上进行霍乱研究）。基于我们现有的海地研究 基础设施，我们建议探讨一系列问题：a）什么是人类的相对贡献， 人与环境对人传播导致海地霍乱发生？B）司机是干什么的 霍乱患者中有症状的感染者？（c）环境水库会长期存在吗？（d） 在霍乱弧菌O 1菌株群体中观察到的进化变化的驱动因素是什么？具体 旨在解决这些问题，以及相关的工作假设，如下： 具体目标1：利用家庭研究探索霍乱传播途径、无症状感染率、 疾病和临床疾病的驱动因素。（a）在海地，从环境到人类的迁移路线 传播比人与人之间的传播造成更多的霍乱感染;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相关， 微生物群落和/或ICP 2和可能的其他溶解性霍乱噬菌体的不存在/数量减少。 具体目标2：监测霍乱弧菌O 1的水生环境水库。工作假设： 霍乱弧菌1的水生环境水库将在海地持续至少5年;和B） 缺乏对人类毒力至关重要的基因的霍乱弧菌O 1的环境分离频率将增加 随着时间的推移，环境水库“老化”。 具体目标3：霍乱弧菌O 1菌株的系统动力学分析。（a）环境 分离株代表了微生物的独立、长期贮存群体， 进化和较慢的，尽管是显著的，人口增长，和B）临床和环境菌株 群体经历正向选择，选择由霍乱特异性噬菌体的存在驱动。

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.