Journal article
Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol
MI Alvarez, LC Glover, P Luo, L Wang, E Theusch, SH Oehlers, EM Walton, TTB Tram, YL Kuang, JI Rotter, CM McClean, NT Chinh, MW Medina, DM Tobin, SJ Dunstan, DC Ko
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2017
Abstract
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, f..
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Grants
Awarded by National Science Foundation
Funding Acknowledgements
We thank Samuel I. Miller for early support of this work; T. Y. Chang for thoughtful discussions on cholesterol distribution and trafficking; the clinical staff from the Hospital of Tropical Diseases, Ho Chi Minh City, and Dong Thap Provincial Hospital, Vietnam, who initially diagnosed and studied the patients with typhoid fever; and Dr. Nguyen Thi Hieu from Hung Vuong Obstetric Hospital for the collection of the cord blood controls. M.I.A., L.C.G., P.L., L.W., D.M.T., S.J.D., and D.C.K. were supported by NIH Grants R01AI118903 and K22AI093595. D.C.K. was also supported by a Duke University Whitehead Scholarship and the Butler Pioneer Award. M.I.A. is supported by a National Science Foundation Predoctoral Fellowship. L.C.G. was supported by a Duke Molecular Genetics and Microbiology Summer Undergraduate Research Engagement Fellowship. S.H.O. was supported by an Australian National Health and Medical Research Council CJ Martin Early Career Fellowship, Grant 1053407. S.J.D. and T.T.B.T. were supported by the Wellcome Trust Major Overseas Program in Viet Nam, Grant 089276/Z/09/Z. E.T., Y.-L.K., and M.W.M. were supported by NIH Grants U19 HL069757 and P50 GM115318. J.I.R. was supported by NIH National Center for Advancing Translational Science University of California, Los Angeles Clinical and Translational Science Institute Grant UL1TR001881. C.M.M. was supported by National Institute of Allergy and Infectious Diseases/NIH Grant F30 AI126693. The graphical abstract was generated by itFigures Consulting. Research reported in this publication was supported by the Duke Light Microscopy Core and Flow Cytometry Shared Resource. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding sources.