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Sex-specific Immune Responses to Severe Influenza Virus Infection

对严重流感病毒感染的性别特异性免疫反应

基本信息

批准号：
10310516
负责人：
Jason Edward Shoemaker
金额：
$ 14.85万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310516
关键词：
Address Affect Age-Years Animal Model Automobile Driving Avian Influenza Avian Influenza A Virus Biological Biological Process Birds Blood California Cells Cessation of life Characteristics Complex Computer Analysis Computer Models Data Disease Outcome Epidemiology Estradiol Experimental Models Female Foundations Future Gonadal Steroid Hormones Growth Hormones Hospitalization Immune Immune response Immune system Immunologics Infection Infiltration Inflammation Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Influenza A virus Innate Immune System Interferons Kinetics Knowledge Link Lung Lung immune response Markov Chains Measures Mediating Modeling Molecular Morbidity - disease rate Mus Outcome Pathogenicity Pathology Patients Predisposition Pregnant Women Production Proteins Pulmonary Inflammation Pulmonary Pathology Reaction Regulation Research Research Personnel Severities Severity of illness Speed Study models System Time Tissues Training Translations Validation Viral Pathogenesis Virulence Virulent Virus Woman base cohort computer studies cytokine cytokine release syndrome dynamic system experience holistic approach human female human male immunopathology immunoregulation improved improved outcome in vivo influenza infection influenzavirus innate immune function insight macrophage male male sex hormones mathematical model men mortality mouse model novel pandemic disease pathogenic virus programs respiratory response seasonal influenza secondary outcome sex trafficking young adult

项目摘要

Sex-specific Immune Responses to Severe Influenza Virus Infection ABSTRACT Men and women experience influenza virus infection differently, with women often experiencing a more severe infection. Lung immunopathology is a major contributing factor to influenza virus disease severity and has been linked to differential disease outcomes in men and women. The differences between male and female immune responses during infection are the immune response dynamics, i.e. the speed and magnitude of the reaction of key immune molecules and cells to the virus. These dynamics are regulated by the molecular and cellular interactions that comprise the lung immune system, and it has been shown that lung immune dynamics can be altered in women by altering levels of circulating sex steroids (estradiol) to affect lung inflammation and overall infection severity. Here, we propose an experimental and computational modeling study to quantify the differential immune kinetics that drive the distinct lung immunopathological outcomes observed between men and women. Human male and female infection outcomes have been recapitulated in mouse models. We will infect male and female mice with a moderate pandemic H1N1 virus and a deadly avian influenza virus, collect dynamic immunologic and hormone data, and train mathematical models to the data to quantify the immune kinetics regulating the differential dynamic lung immune responses observed between the sexes. The immunologic data will include major cytokines and immune cells with established significance to virus clearance and respiratory tissue inflammation. Successful completion of the research program will provide the first sex- specific mathematical models of influenza-induced immune responses, the first mathematical models of the avian influenza induced immune response, and the first mathematical models quantifying the impact of sex hormones on lung immune regulation in females. By quantifying which immune kinetics are different between males and females during moderately and severely pathogenic infections, we will generate novel hypotheses on the molecular/cellular origins of lung immunopathology during influenza infection and provide quantitative evidence on whether mechanisms promoting severe lung pathology are dependent on sex, virulence of the virus, or both factors. And quantifying the relationship between sex hormones and lung immune activity in females may provide insight into the mechanisms associated with the increased susceptibility experienced by pregnant women during severe influenza virus infection.

严重流感病毒感染的性别特异性免疫反应