ZFIN ID: ZDB-PUB-170823-7
Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.
Alvarez, M.I., Glover, L.C., Luo, P., Wang, L., Theusch, E., Oehlers, S.H., Walton, E.M., Tram, T.T.B., Kuang, Y.L., Rotter, J.I., McClean, C.M., Chinh, N.T., Medina, M.W., Tobin, D.M., Dunstan, S.J., Ko, D.C.
Date: 2017
Source: Proceedings of the National Academy of Sciences of the United States of America   114(37): E7746-E7755 (Journal)
Registered Authors: McClean, Colleen, Oehlers, Stefan, Tobin, David
Keywords: Salmonella pathogenicity island 1, ezetimibe, lymphoblastoid cell line, phosphoinositide, single nucleotide polymorphism
MeSH Terms:
  • Cell Line, Tumor
  • Cholesterol/genetics
  • Cholesterol/metabolism
  • Ezetimibe
  • Genetic Variation/genetics
  • Genome-Wide Association Study
  • Humans
  • Membrane Proteins/genetics*
  • Membrane Proteins/metabolism*
  • Polymorphism, Single Nucleotide
  • Salmonella/genetics
  • Salmonella/pathogenicity
  • Salmonella typhi/genetics*
  • Salmonella typhi/metabolism
  • Salmonella typhi/pathogenicity
  • Typhoid Fever/metabolism
  • Typhoid Fever/physiopathology
  • Virulence/genetics
PubMed: 28827342 Full text @ Proc. Natl. Acad. Sci. USA
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.