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

据估计，1918年的流感大流行在全世界每20人中就有1人死亡。甲型流感病毒（IAV） 对于美国每年约3000万的感染者来说，感染通常不会引起如此严重的疾病 （2014-2015年）。然而，IAV的易感性和严重性存在广泛差异， 无症状感染（~16%）至死亡（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。一个关键的宿主因素， IAV感染的异质性是生物学性别。对于儿童和老年人，男性更有可能 患有严重疾病，而育龄妇女的病情更严重。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 鉴定调节人类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。在本补充文件中，我们建议使用两个通用 基金资源，以扩大对IAV感染期间性别差异的生物学理解， 并确定我们的发现在所有人体组织中的普遍性。 在第一个补充目的，我们将使用LINCS了解性别差异的反应，以IAV 感染细胞和人类志愿者。LINCS签名数据库，如在iLINCS中实现的 门户网站，将被利用来确定驱动男性或女性偏向基因表达的关键基因， IAV感染。具体地，查询LINCS CGS（共有基因敲低签名）和LINCS基因敲低签名。 过表达特征将揭示基因，当敲除或过表达时， 在IAV感染后的男性和女性淋巴母细胞样细胞系（LCL）和志愿者中观察到。等 这些特征可能揭示了信号通路，可以解释IAV期间观察到的一些性别差异。 感染细胞和人类。此外，使用化学扰动剂签名的LINCS分析将揭示小的 基因表达变化的分子逆转剂和模拟剂，将作为 药理学靶向，以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来确定性别偏向基因和表达数量性状基因座（sb- 基因和sb-eQTLs）。在家长补助金中，我们确定某人- IAV感染的LCL中以及来自人攻击的全血和鼻刮液中的基因和sb-eQTL 志愿者我们将使用GTEx来确定是否在IAV感染的LCL中鉴定到sb-gene和sb-eQTL， 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， 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 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.