Sex Differences in Protective Immunity Against Influenza A Viruses

描述（由申请方提供）：已记录人类甲型流感病毒感染的发生率和严重程度存在性别差异。虽然男性的接触率通常较高，但据报道，女性接触致病性甲型流感病毒后的死亡率较高。据报道，在对流感病毒疫苗的反应方面也存在性别差异，女性在接种疫苗后的抗体反应一直高于男性，并出现更频繁和更严重的副作用。小动物模型对于建立介导为什么男性和女性对流感病毒感染和疫苗接种的反应不同的机制至关重要。在初次接种小鼠适应性甲型流感病毒A/PR/8/34（PR 8; H1N1）或A/HK/68（HK 68; H3 N2）后，雌性小鼠比雄性小鼠产生更高的炎症和体液免疫应答。我们的初步数据进一步表明，女性对甲型流感病毒的免疫力提高代表了免疫应答之间的微妙平衡，赋予保护或引起病理。本提案的目的是开发一种小动物模型，以检验以下假设：对异亚型甲型流感病毒攻击的保护性免疫力在性别之间存在差异，并受性类固醇激素调节。在具体目标1中，我们将确定女性中的中和抗体应答、病毒特异性T细胞应答和针对致死性甲型流感病毒攻毒的保护作用是否大于男性。男性和女性是否差异依赖于适应性免疫细胞的子集，以保护免受致命的甲型流感病毒感染还没有记录，因此，我们还建议比较异性亚型的免疫反应之间的男性和女性小鼠缺乏特定的适应性免疫细胞群体。如果与男性相比，女性的保护性异亚型免疫力升高，则雌激素和/或孕激素可能增强，雄激素可能抑制针对异亚型甲型流感病毒攻击的适应性免疫力。在具体目标2中，我们将通过操纵体内性类固醇浓度并确定对体液和细胞介导的免疫的影响以及对致死性甲型流感病毒攻击的保护来检验这一假设。这是一系列高风险-高回报的实验，因为迄今为止还没有数据评估甲型流感病毒感染对异亚型免疫的性别特异性诱导。然而，证明女性产生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意义，因为这可以解释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生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介导为什么男性和女性对流感病毒感染和疫苗接种的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应答是否能使女性比男性更好地抵御致病性甲型流感病毒的攻击，以及这些差异在多大程度上是由性类固醇介导的，这可能会为为什么对大流行性甲型流感病毒的应答在性别和妊娠期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.