Impacts of human and bacterial natural genomic diversity on cholera disease severity

Cholera is a diarrheal disease caused by the waterborne bacterium Vibrio cholerae that has caused devastating pandemics and mortality throughout human history. Today, cholera causes over 100,000 deaths every year. Despite extensive study, it is still difficult to predict cholera outbreaks or virulence within individuals. Cholera vaccines exist, but are less than 60% effective, and do not confer long-term immunity. Remarkably, some people exposed to V. cholerae do not become ill and instead become asymptomatic carriers, capable of transmitting the infection. My team will study cholera patients and their household contacts in Bangladesh, where cholera is endemic. Cholera patients are treated by doctors, and most recover. Their contacts have a high risk (~20%) of being infected with V. cholerae, and ~75% of those infected go on to develop symptomatic cholera. By prospectively sampling both cholera patients and their at-risk contacts, we can follow the transition from asymptomatic to symptomatic cholera and identify risk factors. The risk factors measured in our study include mutations in the human or V. cholerae genome, human immune responses, and potentially protective bacteria in the gut microbiome. V. cholerae mutations can occur during an infection, and may help V. cholerae evade the human immune system, or allow it to cause more severe disease. However, even if mutations can benefit V. cholerae on the short term (within one patient), they might be "evolutionary dead-ends" if they hinder its ability to transmit to new patients. Our study will allow us to identify such dead-ends, which could eventually be exploited to reduce cholera transmission. V. cholerae mutations associated with desired outcomes (e.g. strong immune responses, less severe disease and less transmission) could eventually be used in new vaccines.