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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.

项目总结/文摘