Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol

摘要: Risk, severity, and outcome of infection depend on the interplay pathogen virulence host susceptibility. Systematic identification genetic susceptibility to is being undertaken through genome-wide association studies, but how expeditiously move from differences functional mechanisms unclear. Here, we use molecular, cellular, human disease traits experimental validation demonstrate that variation affects expression VAC14, a phosphoinositide-regulating protein, influence Salmonella enterica serovar Typhi (S Typhi) infection. Decreased VAC14 increased plasma membrane cholesterol, facilitating docking invasion. This at cellular level manifests as typhoid fever in Vietnamese population. Furthermore, treating zebrafish with cholesterol-lowering agent, ezetimibe, reduced S Typhi. Thus, coupling multiple studies mechanistic dissection revealed regulates invasion may open doors new prophylactic/therapeutic approaches.