Human genetic variation inVAC14regulatesSalmonellainvasion and typhoid fever through modulation of cholesterol

Abstract

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