Cellular and Molecular Mediators of Hantavirus Infection

汉坦病毒是一种人畜共患病原体，由广泛的啮齿类宿主物种携带，在地理上具有多样性，并引起人类疾病，目前尚无治愈方法。该建议的主要目标是更好地阐明介导宿主对汉坦病毒感染反应的细胞和分子机制。由于疾病预防控制中心将汉坦病毒归类为潜在的生物制剂，因此需要研究介导宿主对感染者易感性的机制，以开发适当的抗感染疗法。汉坦病毒感染的性别差异在人类和几种啮齿动物储库物种中有记录，其中男性比女性感染更多。虽然汉坦病毒感染的性别差异可能反映了行为的二型性，如啮齿动物的攻击性或人类的职业，但最近的研究表明， 我们实验室的数据表明，两性对感染和病毒复制的免疫反应不同。接种首尔病毒后（即，挪威大鼠中天然存在的汉坦病毒），雄性大鼠表现出更高的抗体应答，通过更多途径释放病毒的时间更长，并且在靶器官中存在更多的病毒RNA拷贝，例如 肺，比女性。抗病毒转录因子（例如，eIF-2 α、NF-KappaB、IRF和STAT）在女性中高于男性。与男性相比，女性中转录因子（例如NF-κ B）的上调可能是女性中编码促炎性、趋化性和抗病毒蛋白的基因表达升高的基础。汉坦病毒感染的性别差异可能反映了类固醇受体信号通路对NF-κ B介导的信号转导的影响。本研究的主要目的是检验类固醇激素（包括雄激素、雌激素和糖皮质激素）通过影响细胞信号传导途径介导首尔病毒感染的性别差异的假设。 该提案的目的将通过以下方式实现：1）表征在感染的急性和持续阶段期间编码促炎、抗病毒和趋化蛋白的基因的表达和翻译的性别差异; 2）在发育期间的不同时间操纵性类固醇，以确定是否表达和翻译基因， 编码促炎、抗病毒和趋化蛋白的基因受性类固醇的影响; 3）评估编码促炎、抗病毒和趋化蛋白的基因的表达和翻译是否存在性别差异 是由糖皮质激素受体介导的途径中的二型性介导的。总之，这些研究将提供一个全面的分析，类固醇激素和基因编码的免疫调节蛋白如何相互作用，影响性别差异的表型反应，以感染性疾病，并可能有助于治疗的发展， 在两性中都能成功的出血热病毒。

Hantaviruses are zoonotic agents that are carried by a wide range of rodent host species, are geographically diverse, and cause human disease for which there is currently no cure. The primary goal of this proposal is to better elucidate the cellular and molecular mechanisms mediating host responses to hantavirus infection. Because the CDC classifies hantaviruses as potential biological agents, studies that examine the mechanisms mediating host susceptibility to infectior are required for developing adequate therapies against infection. Sex differences in hantavirus infection are documented in humans and in several rodent reservoir species in which more males are infected than females. Although sex differences in hantavirus infection may reflect dimorphisms in behaviors, such as aggression in rodents or occupation in humans, recent data from our laboratory illustrate that immune responses against infection and virus replication differ between the sexes. After inoculation with Seoul virus (i.e., the naturally occurring hantavirus in Norway rats), male rats exhibit higher antibody responses, shed virus longer and through more routes, and have more viral RNA copies present in target organs, such as the lungs, than females. The expression of antiviral transcriptional factors (e.g., eIF-2alpha, NF-KappaB, IRF, and STAT) is higher in females than males. Upregulation of transcriptional factors, e.g. NF-KappaB, in females may underlie the elevated expression of genes that encode for proinflammatory, chemotactic, and antiviral proteins in females compared with males. Sex differences in hantavirus infection may reflect the effects of steroid receptor signaling pathways on NF-KappaB-mediated signal transduction. The primary aim of this research proposal is to test the hypothesis that steroid hormones, including androgens, estrogens, and glucocorticoids, mediate sex differences in Seoul virus infection through effects on cell signaling pathways. The aims of this proposal will be met by: 1) characterizing sex differences in the expression and translation of genes thal encode for proinflammatory, antiviral, and chemotactic proteins during the acute and persistent phases of infection; 2) manipulating sex steroids at different times during development, to determine if the expression and translation of genes that encode for proinflammatory, antiviral, and chemotactic proteins are influenced by sex steroids; and 3) assessing whether sex differences inthe expression and translation of genes that encode for proinflammatory, antiviral, and chemotactic proteins are mediated by dimorphisms in glucocorticoid receptor-mediated pathways. Taken together, these studies will provide a comprehensive analysis of how steroid hormones and genes that encode for immunoregulatory proteins interact to affect sex differences in phenotypic responses to infectious diseases and may assist in the development of treatments for qemorrhagic fever viruses that will be successful in both sexes.