Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol
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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 to Salmonella enterica serovar Typhi (S. Typhi) infection. Decreased VAC14 expression increased plasma membrane cholesterol, facilitating Salmonella docking 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 to S. Typhi. Thus, coupling multiple genetic association studies with mechanistic dissection revealed how VAC14 regulates Salmonella invasion and typhoid fever susceptibility and may open doors to new prophylactic/therapeutic approaches.
Published Version (Please cite this version)10.1073/pnas.1706070114
Publication InfoAlvarez, MI; Chinh, NT; Dunstan, Sarah J; Glover, LC; Ko, Dennis; Kuang, Y; ... Wang, L (2017). Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol. Proceedings of the National Academy of Sciences. 10.1073/pnas.1706070114. Retrieved from http://hdl.handle.net/10161/15352.
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Assistant Professor in Molecular Genetics and Microbiology
Using Pathogens to Decipher Genetic Variation Connecting Cell Biology and Disease SusceptibilityDespite improvements in public health, advancements in vaccines, and the development of many classes of antibiotics, infectious disease is still responsible for over a quarter of all deaths worldwide. However, even for the most devastating of pandemics, individuals demonstrate a large variability in the severity of infection. The long-term goal of the lab is to understand the ge