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

利用病原体宿主网络来识别呼吸道感染期间的病毒特异性和雌二醇调节机制

• 批准号: 10741119
• 负责人: Jason Edward Shoemaker
• 金额: $ 25.35万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-09 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741119
• 关键词: 2019-nCoV; Address; Adoption; Affect; Age Years; Algorithms; Automobile Driving; Binding; Bioinformatics; COVID-19; CRISPR screen; Cells; Cessation of life; Code; Communicable Diseases; Communities; Computer Analysis; Data; Data Set; Development; Disease; Drug resistance; Epidemiology; Epithelial Cells; Estradiol; Female; Future; Gene Expression; Genomics; Goals; Gonadal Steroid Hormones; Hormones; Hospitalization; Human; Immune; Immune response; Infection; Infectious Diseases Research; Inflammatory; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Integration Host Factors; Knowledge; Link; Mediating; Molecular; Morbidity - disease rate; Nasal Epithelium; National Institute of Allergy and Infectious Disease; Natural regeneration; Nose; Pathway interactions; Patients; Policies; Process; Proteins; Publishing; Research; Respiratory Tract Infections; Signal Transduction; Small Interfering RNA; Time; Validation; Viral Load result; Virus; Virus Replication; Woman; Work; cohort; drug candidate; effectiveness evaluation; experience; human data; in silico; influenza infection; influenzavirus; mathematical model; men; molecular drug target; mortality; novel; pandemic disease; pathogen; patient variability; pressure; programs; respiratory; respiratory infection virus; respiratory virus; response; seasonal influenza; secondary analysis; sex; therapeutic candidate; therapeutic target; therapy development; virus host interaction; whole genome; young adult

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.

抽象的 呼吸道病毒，例如流感和 SARS-CoV-2，与人类不同的分子途径相互作用 细胞促进病毒复制并改变免疫活性 当考虑患者群体变异性和发病率时。 对于某些流感病毒感染，女性的死亡率往往高于男性，2009 年的例证就是如此 H1N1 流感大流行。雌二醇是一种主要的性激素，已被证明会影响特定性别的病毒复制。 然而，关于不同病毒促进感染和改变的途径仍然未知。 免疫活性或什么途径将雌二醇活性与病毒复制联系起来。 开发生物信息学算法和 NIAID 支持的已发布数据集，以揭示新途径 以及参与流感病毒和 SAR-CoV-2 感染（目标 1）以及呼吸道感染的分子 来自女性并用雌二醇处理的细胞（目标 2）。更具体地说，我们将使用两个动态网络。 微扰算法 ProTINA 和 DeltaNeTS+，用于创建细胞内的动态数学模型 将应用信号传导来预测重要的疾病调节剂。 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。 2，我们已经鉴定了女性捐赠者感染流感的鼻细胞的基因表达数据 我们将验证 ProTINA 和 DeltaNeTS+ 识别病毒宿主因子的能力。 验证后，我们将使用已发表的基于 siRNA 和 CRISPR 的筛选结果进行复制。 对已确定的最重要的蛋白质进行深入表征，以产生关于该蛋白质的新假设 参与不同呼吸道病毒感染或与雌二醇相互作用的宿主途径 感染。