Human Genetic Variation Regulating Transcriptional Response and Cellular Susceptibility to Influenza

项目总结/摘要 据估计，有5000万至1亿人（约占全球人口的5%）死于1918年流感大流行。 虽然流感感染通常不会引起如此严重的疾病，但在美国，每年约有3000万人感染流感。 仅美国（2014-2015年）。然而，流感的易感性和严重程度存在很大差异， 从无症状感染（~16%）到死亡（2014-2015年为0.2%）。这些分歧的出现源于这些 暴露、环境、流感遗传学和人类遗传学的复杂相互作用。 我的实验室的总体目标是了解人类遗传多样性如何调节疾病的易感性和严重性。 感染.遗传差异深刻影响易感性的著名例子包括镰状细胞等位基因 针对疟疾的保护和针对HIV的CCR 5缺失保护。这种遗传差异可能导致 对发病机制、药物靶点（如CCR 5抑制剂）和更个性化的护理的见解。对于流感， 最令人信服的是，一种常见的遗传变异在一个位点上影响流感的严重程度（IFITM 3） 在复杂的流感病毒生命周期中调节一个步骤（胞质进入）。我们假设其他人类 遗传差异影响流感感染，可以通过测量个体间的变异来确定， 细胞感染表型。为了便于识别影响细胞感染表型的SNP，我们 开发并验证了一种基于细胞的GWAS方法，称为Hi-HOST。确定为重要的SNP 然后可以使用已经完成的方法检查Hi-HOST的流感感染与人类感染的相关性， 人类流感挑战研究和基于人群的研究。我们认为人类主体的交集 细胞系数据有助于发现新的途径和易感性的遗传决定因素。 该项目将产生人类遗传变异如何影响转录的高分辨率分析， 细胞表型和流感暴露后的人类疾病。我们将通过1） 鉴定赋予对流感感染的细胞和分子表型的抗性/易感性的人类SNP， 包括进入、复制、细胞死亡、细胞因子水平和宿主转录应答，2）确定 在健康志愿者的流感攻击期间，SNP对宿主转录的影响，以及3）整合 生成细胞和人类挑战数据集，以生成和测试与转录相关的假设 反应和细胞易感性。了解这些差异可能会导致新的诊断方法 识别高危个体和新的治疗策略。

Project Summary/Abstract It is estimated that 50-100 million people (~5% of the global population) died from the 1918 influenza pandemic. While influenza infections usually do not cause such severe disease, ~30 million are infected every year in the United States alone (2014-2015). However, there are broad differences in influenza susceptibility and severity, with outcomes from asymptomatic infections (~16%) to death (0.2% in 2014-2015). These differences arise from the complex interplay of exposure, environment, influenza genetics, and human genetics. The overall goal of my lab is to understand how human genetic diversity regulates susceptibility and severity of infections. Famous examples of genetic differences that profoundly impact susceptibility include sickle cell allele protection against malaria and CCR5 deletion protection against HIV. Such genetic differences can lead to insights on pathogenesis, drug targets (e.g. CCR5 inhibitors), and more personalized care. For influenza, common genetic variation has been most convincingly shown to influence flu severity at a single locus (IFITM3) that regulates a single step (cytosolic entry) in the complex influenza life cycle. We hypothesize that other human genetic differences affect influenza infection and can be identified through measuring inter-individual variation in cellular infection phenotypes. To facilitate identification of SNPs that affect cellular infection phenotypes, we developed and validated a cell-based GWAS approach called Hi-HOST. SNPs identified as important for influenza infection by Hi-HOST can then be examined for relevance in human infection using already completed human flu challenge studies and population-based studies. We propose that the intersection of human subject and cell line data facilitates discovery of novel pathways and genetic determinants of susceptibility. This project will generate a high resolution analysis of how human genetic variants impact transcription, cellular phenotypes, and human disease following influenza exposure. We will accomplish this through 1) identifying human SNPs that confer resistance/susceptibility to cellular and molecular phenotypes of flu infection, including entry, replication, cell death, cytokine levels, and host transcriptional responses, 2) determining the impact of SNPs on host transcription during influenza challenge of healthy volunteers, and 3) integrating the generated cellular and human challenge datasets to generate and test hypotheses linking transcriptional response and cellular susceptibility. Understanding these differences could lead to new diagnostic approaches in identifying at-risk individuals and novel therapeutic strategies for treatment.