Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710.
Children's Hospital Oakland Research Institute, Oakland, CA 94609.
Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):E7746-E7755. doi: 10.1073/pnas.1706070114. Epub 2017 Aug 21.
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 serovar Typhi ( Typhi) infection. Decreased VAC14 expression increased plasma membrane cholesterol, facilitating 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 Typhi. Thus, coupling multiple genetic association studies with mechanistic dissection revealed how VAC14 regulates invasion and typhoid fever susceptibility and may open doors to new prophylactic/therapeutic approaches.
感染的风险、严重程度和结果取决于病原体毒力和宿主易感性的相互作用。通过全基因组关联研究正在系统性地鉴定感染的遗传易感性，但如何迅速从遗传差异转移到功能机制尚不清楚。在这里，我们使用分子、细胞和人类疾病特征的遗传关联以及实验验证来证明遗传变异影响磷酸肌醇调节蛋白 VAC14 的表达，从而影响对血清型伤寒（伤寒）感染的易感性。VAC14 表达的降低增加了质膜胆固醇，促进了停泊和入侵。这种细胞水平的易感性增加表现为越南人群中伤寒的易感性增加。此外，用降低胆固醇的药物依泽替米贝治疗斑马鱼可降低对伤寒的易感性。因此，将多个遗传关联研究与机制剖析相结合，揭示了 VAC14 如何调节入侵和伤寒易感性，并可能为新的预防/治疗方法开辟道路。
