Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.
Published
Journal Article
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.
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Duke Authors
Cited Authors
- Alvarez, MI; Glover, LC; Luo, P; Wang, L; Theusch, E; Oehlers, SH; Walton, EM; Tram, TTB; Kuang, Y-L; Rotter, JI; McClean, CM; Chinh, NT; Medina, MW; Tobin, DM; Dunstan, SJ; Ko, DC
Published Date
- September 12, 2017
Published In
Volume / Issue
- 114 / 37
Start / End Page
- E7746 - E7755
PubMed ID
- 28827342
Pubmed Central ID
- 28827342
Electronic International Standard Serial Number (EISSN)
- 1091-6490
Digital Object Identifier (DOI)
- 10.1073/pnas.1706070114
Language
- eng
Conference Location
- United States