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

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3000万感染者来说，感染通常不会导致如此严重的疾病 单单(2014-2015)。然而，IAV的易感性和严重性有很大的差异，其结果是 无症状感染(约16%)致死(2014-2015年为0.2%)。这些差异源于情结 暴露、环境、IAV遗传和宿主因素的相互作用。一个关键的宿主因素，有助于 IAV感染的异质性是生物性。对于儿童和老年人来说，男性更有可能 经历严重的疾病，而育龄女性的严重程度更高。我们假设性行为 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，我们是 确定调节人体IAV负荷和宿主反应的基因表达的性别差异 细胞、IAV挑战志愿者和自然种群。在本副刊中，我们建议使用两种常见的 基金资源，以扩大对IAV感染期间性别差异的生物学理解，这将是 从这项研究中揭示出来，并确定我们的发现在所有人体组织中的普适性。 在第一个补充目标中，我们将使用LINCS来了解IAV反应中的性别差异 在细胞和人类志愿者中感染。Lincs签名数据库，如在iLINCS中实施的 门户，将被用来识别驱动男性或女性偏向基因表达的关键基因 IAV感染。具体地说，查询Lincs CGS(共识基因敲除签名)和Lincs基因 过度表达签名将揭示当被击倒或过度表达时模仿签名的基因 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。是这样的 信号可能揭示信号通路，可以解释IAV期间出现的一些性别差异 细胞和人类中的感染。此外，使用化学微扰特征的LINCS分析将揭示 基因表达变化的分子逆转因子和模仿者，将作为 药物靶向，以改善严重流感感染的预后。在第二个补充目标中，我们将 使用GTEx来确定性别偏向基因和表达数量性状基因座(SB-T)的泛化能力 基因和SB-eQTL)在人体组织中感染IAV。在家长赠款中，我们确定了某人- IAV感染的LCLS和人类全血及鼻腔刮除中的基因和SB-eQTL 志愿者。我们将使用GTEx来确定在IAV感染的LCLS和 来自人类志愿者的全血也适用于其他组织，增加了我们发现的普遍性。 本补充申请建议利用两个共同基金资源，Lincs和GTEx，以增加 家长奖的洞察力和概括性。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。

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.