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Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.

Publication ,  Journal Article
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 ...
Published in: Proc Natl Acad Sci U S A
September 12, 2017

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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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

September 12, 2017

Volume

114

Issue

37

Start / End Page

E7746 / E7755

Location

United States

Related Subject Headings

  • Virulence
  • Typhoid Fever
  • Salmonella typhi
  • Salmonella
  • Polymorphism, Single Nucleotide
  • Membrane Proteins
  • Intracellular Signaling Peptides and Proteins
  • Humans
  • Genome-Wide Association Study
  • Genetic Variation
 

Citation

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Alvarez, M. I., Glover, L. C., Luo, P., Wang, L., Theusch, E., Oehlers, S. H., … Ko, D. C. (2017). Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol. Proc Natl Acad Sci U S A, 114(37), E7746–E7755. https://doi.org/10.1073/pnas.1706070114
Alvarez, Monica I., Luke C. Glover, Peter Luo, Liuyang Wang, Elizabeth Theusch, Stefan H. Oehlers, Eric M. Walton, et al. “Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.Proc Natl Acad Sci U S A 114, no. 37 (September 12, 2017): E7746–55. https://doi.org/10.1073/pnas.1706070114.
Alvarez MI, Glover LC, Luo P, Wang L, Theusch E, Oehlers SH, et al. Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol. Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):E7746–55.
Alvarez, Monica I., et al. “Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.Proc Natl Acad Sci U S A, vol. 114, no. 37, Sept. 2017, pp. E7746–55. Pubmed, doi:10.1073/pnas.1706070114.
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. Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol. Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):E7746–E7755.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

September 12, 2017

Volume

114

Issue

37

Start / End Page

E7746 / E7755

Location

United States

Related Subject Headings

  • Virulence
  • Typhoid Fever
  • Salmonella typhi
  • Salmonella
  • Polymorphism, Single Nucleotide
  • Membrane Proteins
  • Intracellular Signaling Peptides and Proteins
  • Humans
  • Genome-Wide Association Study
  • Genetic Variation