Human Genetic Variation Regulating Transcriptional Response and Cellular Susceptibility to Influenza

人类遗传变异调节转录反应和细胞对流感的易感性

基本信息

批准号：
10217457
负责人：
Dennis Chun-Yone Ko
金额：
$ 19.54万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-09 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217457
关键词：
A549 Affect Alleles Antiviral Agents Blood CCR5 gene Cell Death Cell Line Cells Cessation of life Collaborations Complex Curettage procedure Data Data Set Detection Disease Drug Targeting Environment Epithelial Cells Gene Expression Generations Genes Genetic Genetic Determinism Genetic Transcription Genetic Variation Genome Genotype Goals HIV Heritability Human Human Cell Line Human Genetics Immune Immune response Individual Individual Differences Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H3N2 Subtype Influenza A virus Interferon Activation Interferons Lead Life Life Cycle Stages Link Lung Malaria Measures Nose Outcome Parents Pathogenesis Pathway interactions Phenotype Population Population Study Predisposition Quantitative Trait Loci Reproducibility Resistance Resolution Respiratory Tract Infections Risk Severities Severity of illness Sickle Cell Signal Transduction Testing United States Validation Variant Virus Diseases Work base cytokine flu genetic variant genome wide association study genome-wide healthy volunteer human disease human subject influenza infection inhibitor/antagonist insight inter-individual variation lymphoblastoid cell line molecular phenotype novel novel diagnostics novel therapeutic intervention offspring pandemic disease pandemic influenza personalized care programs response trait transcriptome sequencing treatment strategy

项目摘要

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.

项目概要/摘要据估计，1918 年流感大流行导致 50-1 亿人（约占全球人口的 5%）死亡。虽然流感感染通常不会引起如此严重的疾病，但每年约有 3000 万人被感染仅美国（2014-2015 年）。然而，流感的易感性和严重程度存在很大差异，结果从无症状感染（~16%）到死亡（2014-2015 年为 0.2%）。这些差异源于暴露、环境、流感遗传学和人类遗传学之间复杂的相互作用。我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。深刻影响易感性的遗传差异的著名例子包括镰状细胞等位基因预防疟疾和 CCR5 缺失预防艾滋病毒。这种遗传差异可能导致关于发病机制、药物靶点（例如 CCR5 抑制剂）和更个性化护理的见解。对于流感，最令人信服的是，常见的遗传变异会影响单个位点的流感严重程度 (IFITM3) 它调节复杂的流感生命周期中的单个步骤（细胞质进入）。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差异来识别细胞感染表型。为了促进影响细胞感染表型的 SNP 的鉴定，我们开发并验证了一种基于细胞的 GWAS 方法，称为 Hi-HOST。被认为重要的 SNP 然后可以使用已经完成的数据检查 Hi-HOST 感染的流感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。我们建议人类主体的交叉点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。该项目将对人类遗传变异如何影响转录进行高分辨率分析，细胞表型和流感暴露后的人类疾病。我们将通过 1) 来实现这一点识别赋予流感感染细胞和分子表型抵抗力/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反应，2) 确定健康志愿者流感攻击期间 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，以生成和测试连接转录的假设反应和细胞敏感性。了解这些差异可能会带来新的诊断方法识别高危人群和新的治疗策略。