Sex Differences in Protective Immunity Against Influenza A Viruses

描述(由申请人提供)：人类甲型流感病毒感染的发病率和严重程度的性别差异已有记录。虽然男性的接触率往往较高，但据报道，女性在接触致病性甲型流感病毒后的死亡率较高。对流感病毒疫苗的反应也存在性别差异，女性在接种疫苗后始终会产生更高的抗体反应，并出现比男性更频繁和更严重的副作用。小动物模型对于建立调节男性和女性对流感病毒感染和疫苗接种反应不同的机制至关重要。在初次接种小鼠适应的甲型流感病毒A/PR/8/34(PR8；H1N1)或A/HK/68(HK68；H3N2)后，雌性小鼠比雄性小鼠获得更高的炎症和体液免疫应答。我们的初步数据进一步显示，女性对甲型流感病毒免疫力的提高代表了免疫反应提供保护或导致病理之间的微妙平衡。这项提议的目标是开发一个小动物模型，以检验对异型甲型流感病毒挑战的保护性免疫在性别之间存在差异，并受性类固醇激素调节的假设。在具体目标1中，我们将确定女性的中和抗体反应、病毒特异性T细胞反应和对致死性甲型流感病毒攻击的保护力是否比男性更大。雄性和雌性是否不同地依赖适应性免疫细胞亚群来预防致命的甲型流感病毒感染还没有文献记载；因此，我们还建议比较缺乏特定适应性免疫细胞群的雄性和雌性小鼠之间的异亚型免疫反应。如果女性的保护性异型免疫高于男性，那么雌激素和/或孕激素可能会增强，而雄激素可能会抑制针对异型甲型流感病毒的获得性免疫。在特定的目标2中，我们将通过操纵性类固醇在体内的浓度来检验这一假设，并确定其对体液和细胞介导的免疫以及对致命性甲型流感病毒攻击的保护作用。这些是一系列高风险-高回报的实验，因为到目前为止还没有数据评估针对甲型流感病毒感染而诱导的性别特异性异型免疫。然而，证明女性启动广泛的保护性免疫反应将对应对每年的流感流行具有重要影响，因为这可能解释了为什么男性的流感发病率高于女性，并受到怀孕的影响。 公共卫生相关性：在人类中，甲型流感病毒感染的发病率和严重程度以及对疫苗接种的反应存在性别差异。小动物模型对于建立调节男性和女性对流感病毒感染和疫苗接种反应不同的机制至关重要。我们将评估亚致死性感染后较高的体液免疫反应是否比男性对致病性甲型流感病毒的攻击具有更强的保护作用，以及这些差异在多大程度上是由性类固醇介导的，这可能为为什么对甲型流感大流行病毒的反应在性别和孕期之间存在差异提供线索。

DESCRIPTION (provided by applicant): Sex differences in the incidence and severity of influenza A virus infection have been documented in humans. Although exposure rates are often higher in men, fatality following exposure to pathogenic influenza A viruses is reportedly higher in women. Sex differences also are reported in response to influenza virus vaccines, with women consistently mounting higher antibody responses and developing more frequent and severe side effects following vaccination than men. Small animal models are critical for establishing the mechanisms mediating why males and females respond differently to influenza virus infection and vaccination. Following primary inoculation with the mouse-adapted influenza A viruses A/PR/8/34 (PR8; H1N1) or A/HK/68 (HK68; H3N2), female mice mount higher inflammatory and humoral immune responses than males. Our preliminary data further reveal that elevated immunity in females against influenza A viruses represents a delicate balance between immune responses conferring protection or causing pathology. The goal of this proposal is to develop a small animal model to test the hypothesis that protective immunity to heterosubtypic influenza A virus challenge differs between the sexes and is modulated by sex steroid hormones. In Specific Aim 1, we will establish whether neutralizing antibody responses, virus-specific T cell responses, and protection against lethal influenza A virus challenge is greater among females than males. Whether males and females differentially rely on subsets of adaptive immune cells for protection against lethal influenza A virus infection has not been documented; thus, we also propose to compare heterosubtypic immune responses between male and female mice devoid of specific adaptive immune cell populations. If protective heterosubtypic immunity is elevated in females compared with males, then estrogens and/or progestins may enhance and androgens may suppress adaptive immunity against heterosubtypic influenza A virus challenge. In Specific Aim 2 we will test this hypothesis by manipulating sex steroid concentrations in vivo and establishing the effects on humoral and cell-mediated immunity as well as protection from lethal influenza A virus challenge. These are a series of high risk-high return experiments because there are no data to date assessing the sex-specific induction of heterosubtypic immunity in response to influenza A virus infection. Demonstrating that females mount a broadly protective immune response, however, will have important implications for dealing with annual epidemics of influenza, as this may explain why the attack rates for influenza are higher in men than in woman and influenced by pregnancy. PUBLIC HEALTH RELEVANCE: Sex differences in the incidence and severity of influenza A virus infection as well as in response to vaccination have been documented in humans. Small animal models are critical for establishing the mechanisms mediating why males and females respond differently to influenza virus infection and vaccination. We will evaluate whether higher humoral immune responses following sublethal infection confers greater protection from challenge with pathogenic influenza A viruses in females compared with males and the extent to which these differences are mediated sex steroids, which may provide clues into why responses to pandemic influenza A viruses differ between the sexes and during pregnancy.