Genetic Contributors to the Impact of Sex on Heterogeneity in Flu Infection

性别对流感感染异质性影响的遗传因素

基本信息

批准号：
10869787
负责人：
Dennis Chun-Yone Ko
金额：
$ 16.14万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-21 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10869787
关键词：
1918 influenza pandemic Area Award Biological Cell Line Cells Cessation of life Chemicals Child Communicable Diseases Comparative Study Complex Consensus Curettage procedure Data Databases Disease Environment Epithelial Cells Female Female of child bearing age Funding Gene Expression Gene Expression Profile Genes Genetic Genetic Variation Genome Genotype-Tissue Expression Project Heterogeneity Human Human Genetics Human Herpesvirus 4 Human Volunteers Immune response Individual Infection Influenza Influenza A virus Integration Host Factors Lung Lymphocyte Activation Nose Outcome Parents Persons Population Predisposition Quantitative Trait Loci RNA Splicing Reporting Research Resources Respiratory Tract Infections Same-sex Severities Sex Bias Sex Differences Signal Pathway Signal Transduction Source Testing Tissues Transcript United States United States National Institutes of Health Variant Virus Diseases Whole Blood biological sex experience flu human tissue improved improved outcome influenza infection insight knock-down lymphoblastoid cell line male novel therapeutic intervention novel therapeutics overexpression parent grant pharmacologic response sex small molecule therapeutic candidate transcription factor virus genetics volunteer

项目摘要

The 1918 influenza pandemic is estimated to have killed 1 in 20 people worldwide. Influenza A virus (IAV) infections usually do not cause such severe disease for the ~30 million infected every year in the United States alone (2014-2015). However, there are broad differences in IAV 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, IAV genetics, and host factors. A crucial host factor that contributes to heterogeneity of IAV infection is biological sex. For children and older individuals, males are more likely to experience severe disease, while females of child-bearing age have greater severity. We hypothesize that sex differences in gene expression are a major driver of heterogeneity in IAV infection. In the parent award, we are identifying sex-specific differences in gene expression that regulate IAV burden and host response in human cells, IAV challenge volunteers, and natural populations. In this Supplement, we propose to use two Common Fund resources to expand the biological understanding of sex differences during IAV infection that will be revealed from this study and to determine the generalizability of our findings across all human tissues. In the first supplement Aim, we will use LINCS to understand sex differences in the response to IAV infection in cells and human volunteers. The LINCS signatures database, as implemented in the iLINCS portal, will be leveraged to identify the critical genes that drive male- or female-biased gene expression following IAV infection. Specifically, querying the LINCS CGS (consensus gene knockdown signatures) and LINCS gene overexpression signatures will reveal genes that when knocked down or overexpressed mimic signatures observed in male and female lymphoblastoid cell lines (LCLs) and volunteers following IAV infection. Such signatures may reveal signaling pathways that could explain some of the sex differences seen during IAV infection in cells and humans. Further, LINCS analysis using chemical perturbagen signatures will reveal small molecule reversers and mimickers of the gene expression changes that will serve as starting points for pharmacological targeting to improve outcomes in severe flu infection. In the second supplement Aim, we will use GTEx to determine the generalizability of sex-biased genes and expression quantitative trait loci (sb- Genes and sb-eQTLs) during IAV infection across human tissues. In the parent grant, we are identifying sb- Genes and sb-eQTLs in IAV-infected LCLs and in whole blood and nasal curettage from human challenge volunteers. We will use GTEx to determine whether sb-Genes and sb-eQTLs identified in IAV-infected LCLs and whole blood from human volunteers are applicable to other tissues, increasing the generalizability of our findings. This Supplement Application proposes to utilize two Common Fund Resources, LINCS and GTEx, to increase the insight and generalizability of the parent award. Doing so will increase our understanding of the genetic basis for sex differences and could lead to novel therapeutic strategies.

据估计，1918 年的流感大流行导致全球每 20 人中就有 1 人死亡。甲型流感病毒（IAV）对于美国每年约 3000 万人来说，感染通常不会导致如此严重的疾病独自一人（2014-2015）。然而，IAV 的易感性和严重程度存在广泛差异，结果如下：无症状感染者（~16%）导致死亡（2014-2015 年为 0.2%）。这些差异源于复杂的暴露、环境、IAV 遗传学和宿主因素的相互作用。一个重要的宿主因素，有助于 IAV感染的异质性是生物性别。对于儿童和老年人来说，男性更有可能病情较重，育龄女性病情较重。我们假设性基因表达的差异是 IAV 感染异质性的主要驱动因素。在家长奖中，我们识别调节人类 IAV 负荷和宿主反应的基因表达的性别特异性差异细胞、IAV 挑战志愿者和自然群体。在本补充中，我们建议使用两种常见的资助资源以扩大对 IAV 感染期间性别差异的生物学理解，这将是这项研究揭示了这一点，并确定我们的研究结果在所有人体组织中的普遍性。在第一个补充目标中，我们将使用 LINCS 来了解对 IAV 反应的性别差异细胞和人类志愿者的感染。 LINCS 签名数据库，在 iLINCS 中实现门户网站，将用于识别驱动男性或女性偏向基因表达的关键基因甲型肝炎病毒感染。具体来说，查询 LINCS CGS（共识基因敲低签名）和 LINCS 基因过度表达特征将揭示当被敲除或过度表达时模仿特征的基因在 IAV 感染后的男性和女性淋巴母细胞系 (LCL) 和志愿者中观察到。这样的特征可能揭示信号通路，从而解释 IAV 期间观察到的一些性别差异细胞和人体感染。此外，使用化学扰动特征的 LINCS 分析将揭示微小的基因表达变化的分子逆转者和模仿者将作为起点药物靶向改善严重流感感染的结果。在第二个补充目标中，我们将使用 GTEx 确定性别偏向基因和表达数量性状位点 (sb- IAV 感染人体组织期间的基因和 sb-eQTL。在家长补助金中，我们正在确定 sb- IAV 感染的 LCL 以及人类攻击的全血和鼻刮除液中的基因和 sb-eQTL 志愿者。我们将使用 GTEx 来确定是否在 IAV 感染的 LCL 中识别出 sb-Genes 和 sb-eQTL 来自人类志愿者的全血适用于其他组织，增加了我们研究结果的普遍性。本补充申请建议利用两个共同基金资源 LINCS 和 GTEx，以增加家长奖的洞察力和普遍性。这样做将增加我们对遗传基础的理解性别差异并可能导致新的治疗策略。