Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol
| Autor: | Marisa W. Medina, Jerome I. Rotter, Stefan H. Oehlers, David M. Tobin, Elizabeth Theusch, Dennis C. Ko, Yu-Lin Kuang, Trinh T. B. Tram, Eric M. Walton, Liuyang Wang, Colleen M. McClean, Monica I. Alvarez, Sarah J. Dunstan, Nguyen Tran Chinh, Peter M Luo, Luke C. Glover |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
education.field_of_study Salmonella Multidisciplinary Population Genome-wide association study Biology Salmonella typhi medicine.disease_cause medicine.disease Typhoid fever Microbiology 03 medical and health sciences 030104 developmental biology Immunology Genetic variation medicine Genetic predisposition education Pathogen |
| Zdroj: | Proceedings of the National Academy of Sciences. 114 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1706070114 |
| Popis: | Significance Salmonella enterica serovar Typhi ( S . Typhi) causes ∼20 million cases of typhoid fever every year. We carried out a genome-wide association study to identify genetic differences that correlate with the susceptibility of cells from hundreds of individuals to S . Typhi invasion. A SNP in VAC14 was associated with susceptibility to S . Typhi invasion and VAC14 expression. Cells mutated for VAC14 displayed increased S . Typhi docking due to increased plasma membrane cholesterol levels. The same SNP was associated with risk of typhoid fever in a Vietnamese population. Furthermore, treating zebrafish with a cholesterol-lowering drug reduced their susceptibility to S . Typhi infection. Therefore, this work demonstrates the power of coupling multiple genetic association studies with mechanistic dissection for understanding infectious disease susceptibility. |
| Databáze: | OpenAIRE |
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