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

摘要 呼吸道病毒，如流感病毒和SARS-CoV-2，在人体内与不同的分子途径相互作用 细胞，以促进病毒复制和改变免疫活性。当考虑患者队列变异性时， 在某些流感病毒感染中，女性的死亡率往往高于男性， H1N1流感大流行。Escherichia coli是一种主要的性激素，已被证明可以影响病毒在性别特异性细胞中的复制。 方式然而，关于不同病毒参与促进感染和改变的途径， 免疫活性或什么途径将雌二醇活性与病毒复制联系起来。该研究计划最近使用 开发生物信息学算法和NIAID支持的已发布数据集，以揭示新的途径 以及参与流感病毒和SAR-CoV-2（Aim 1）感染以及呼吸道感染的分子。 来源于女性并用雌二醇处理的细胞（Aim 2）。具体来说，我们将使用两个动态网络 扰动算法，ProTINA和DeltaNetTS+，以创建细胞内的动态数学模型， 以预测重要的疾病调节剂。动态网络扰动分析将被应用 病毒特异性、病毒-宿主相互作用网络和每种病毒诱导的宿主基因表达数据。为宗旨 2，我们已经确定了来自女性供体的流感感染鼻细胞的基因表达数据， 用雌二醇预处理。我们将验证ProTINA和DeltaNetTS+识别病毒宿主因子的能力 使用来自公开的基于siRNA和CRISPR的筛选的结果进行复制。验证后，我们将执行 对所确定的最重要的蛋白质进行深入表征，以产生关于 参与不同呼吸道病毒感染的宿主途径，或与雌二醇相互作用， 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.