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.

摘要