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.

Full Text

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 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

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1706070114

Language

  • eng