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

Significance Salmonella enterica serovar Typhi ( S . Typhi) causes ∼20 million cases of typhoid fever every year. We carried out a genome-wide association study to identify genetic differences that correlate with the susceptibility of cells from hundreds of individuals to S . Typhi invasion. A SNP in VAC14 was associated with susceptibility to S . Typhi invasion and VAC14 expression. Cells mutated for VAC14 displayed increased S . Typhi docking due to increased plasma membrane cholesterol levels. The same SNP was associated with risk of typhoid fever in a Vietnamese population. Furthermore, treating zebrafish with a cholesterol-lowering drug reduced their susceptibility to S . Typhi infection. Therefore, this work demonstrates the power of coupling multiple genetic association studies with mechanistic dissection for understanding infectious disease susceptibility.