Sex-specific Immune Responses to Severe Influenza Virus Infection

针对严重流感病毒感染的性别特异性免疫反应 摘要 男性和女性感染流感病毒的情况不同，女性通常经历更严重的 感染。肺部免疫病理是导致流感病毒疾病严重程度的主要因素，一直以来 与男性和女性的疾病结局不同有关。男性和女性免疫的差异 感染期间的反应是免疫反应动态，即反应的速度和大小 病毒的关键免疫分子和细胞。这些动态是由分子和细胞调节的。 组成肺免疫系统的相互作用，已经表明肺免疫动力学可以 通过改变循环性类固醇(雌二醇)水平来改变女性以影响肺部炎症和整体 感染严重程度。在这里，我们提出了一个实验和计算模型研究来量化 差异免疫动力学驱动男性之间观察到的不同的肺免疫病理结果 还有女人。人类男性和女性感染的结果已经在小鼠模型中得到了概括。我们会 用中度大流行H1N1病毒和致命的禽流感病毒感染雄性和雌性小鼠，收集 动态的免疫学和激素数据，并对数据进行数学模型训练以量化免疫 调节不同性别间动态肺免疫反应的动力学。这个 免疫学数据将包括对病毒清除具有既定意义的主要细胞因子和免疫细胞 和呼吸道组织发炎。研究计划的成功完成将提供第一次性行为- 流感诱导的免疫反应的特定数学模型，第一个数学模型 禽流感诱导的免疫反应，以及量化性别影响的第一个数学模型 激素对女性肺部免疫的调节作用。通过量化哪些免疫动力学不同于 男性和女性在中度和重度致病感染期间，我们将产生关于 流感感染过程中肺免疫病理的分子/细胞起源并提供定量 关于促进严重肺部病变的机制是否依赖于性别、病毒毒力、 或者两者兼而有之。量化女性性激素和肺部免疫活性之间的关系可能会 洞察与怀孕易感性增加相关的机制 妇女在严重的流感病毒感染期间。

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.