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.
- 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
- Salmonella pathogenicity island 1, ezetimibe, lymphoblastoid cell line, phosphoinositide, single nucleotide polymorphism
- MeSH Terms
- Cell Line, Tumor
- Genetic Variation/genetics
- Genome-Wide Association Study
- Membrane Proteins/genetics*
- Membrane Proteins/metabolism*
- Polymorphism, Single Nucleotide
- Salmonella typhi/genetics*
- Salmonella typhi/metabolism
- Salmonella typhi/pathogenicity
- Typhoid Fever/metabolism
- Typhoid Fever/physiopathology
- 28827342 Full text @ Proc. Natl. Acad. Sci. USA
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. (2017) Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.. Proceedings of the National Academy of Sciences of the United States of America. 114(37):E7746-E7755.
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.
Errata / NotesThis article is corrected by ZDB-PUB-220906-87 . This article is corrected by ZDB-PUB-220906-88 .
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes