Leveraging Pathogen-Host Networks to Identify Virus-specific and Estradiol-regulated Mechanisms during Respiratory Infection

摘要 呼吸道病毒，如流感和SARS-CoV-2，与人类不同的分子途径相互作用 促进病毒复制和改变免疫活性的细胞。当考虑到患者队列的变异性、发病率 在特定的流感病毒感染中，女性的死亡率往往高于男性，这在2009年就是一个例证 H1N1大流行。雌二醇是一种主要的性激素，已被证明影响特定性别的病毒复制。 举止。然而，关于不同病毒参与促进感染和改变的途径，仍有许多未知之处。 免疫活性或将雌二醇活性与病毒复制联系起来的途径。这个研究程序最近使用了 开发生物信息学算法和NIAID支持的发布数据集，以揭示新的途径 和涉及感染流感病毒和SARS-CoV-2的分子(目标1)和呼吸道感染 来自妇女的细胞，用雌二醇处理(目标2)。更确切地说，我们将使用两个动态网络 微扰算法，ProTINA和DeltaNeTS+，以创建细胞内的动态数学模型 为了预测重要的疾病调节因子而发出信号。将应用动态网络扰动分析 病毒特异性、病毒-宿主相互作用网络和宿主基因表达数据。为了达到目标 2，我们已经从来自女性捐赠者的感染流感的鼻细胞中鉴定出基因表达数据 用雌二醇预处理。我们将验证ProTINA和DeltaNeTS+识别病毒宿主因素的能力 利用已发表的基于siRNA和CRISPR的筛选结果进行复制。在验证之后，我们将执行 对确定的最重要的蛋白质进行深入的表征，以产生关于 感染不同呼吸道病毒或与雌二醇相互作用的宿主途径 感染。

ABSTRACT Respiratory viruses, such as influenza and SARS-CoV-2, interact with distinct molecular pathways in human cells to promote virus replication and alter immune activity. When considering patient cohort variability, morbidity and mortality are often higher for women than men for select influenza virus infections, exemplified in the 2009 H1N1 pandemic. Estradiol, a major sex hormone, has been shown to impact virus replication in a sex-specific manner. Yet much remains unknown as to the pathways different viruses engage to promote infection and alter immune activity or what pathways link estradiol activity to virus replication. This research program uses recently developed bioinformatics algorithms and NIAID-supported, published datasets in order to reveal new pathways and molecules involved in infection with influenza viruses and SAR-CoV-2 (Aim 1) and in infection in respiratory cells derived from women and treated with estradiol (Aim 2). More specifically, we will use two dynamic network perturbation algorithms, ProTINA and DeltaNeTS+, to create dynamic mathematical models of intracellular signaling in order to predict important disease modulators. Dynamic network perturbation analysis will be applied to virus-specific, virus-host interaction networks and host gene expression data induced by each virus. For Aim 2, we have identified gene expression data from influenza-infected nasal cells from female donors that are pretreated with estradiol. We will validate ProTINA’s and DeltaNeTS+ ability to identify host factors of virus replication using results from published siRNA- and CRISPR-based screens. After the validation, we will perform an in-depth characterization of the most significant proteins identified in order to generate new hypothesis on the host pathways that are involved in infection with different respiratory viruses or that interact with estradiol during infection.