Cellular and Molecular Mediators of Hantavirus Infection

汉坦病毒是一种人畜共患病病原体，由多种啮齿动物宿主携带，具有地理多样性，可引起人类疾病，目前尚无治愈方法。这项建议的主要目的是更好地阐明介导宿主对汉坦病毒感染的反应的细胞和分子机制。由于疾控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，以开发适当的感染治疗方法。汉坦病毒感染的性别差异在人类和几个啮齿动物宿主物种中有记录，在这些物种中，雄性比雌性感染更多。尽管汉坦病毒感染的性别差异可能反映了行为的二相性，如啮齿动物的攻击性或人类的职业，最近 我们实验室的数据表明，对感染和病毒复制的免疫反应在性别之间存在差异。在接种首尔病毒(即挪威大鼠身上自然产生的汉坦病毒)后，雄性大鼠表现出更高的抗体反应，释放病毒的时间更长，途径更多，靶器官中存在更多的病毒RNA拷贝，如 肺部，而不是雌性。抗病毒转录因子(如eIF-2α、NF-kappaB、IRF和STAT)在女性中的表达高于男性。与男性相比，女性体内转录因子，如核因子-kappaB的上调可能是女性致炎、趋化和抗病毒蛋白编码基因表达增加的基础。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核因子-kappaB介导的信号转导的影响。这项研究建议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，通过影响细胞信号通路在首尔病毒感染中调节性别差异的假设。 这项建议的目标将通过：1)表征在感染的急性和持续阶段，促炎症、抗病毒和趋化蛋白编码的基因的表达和翻译的性别差异；2)在发育的不同时期操纵性类固醇，以确定是否 促炎、抗病毒和趋化蛋白的编码受性类固醇的影响；以及3)评估致炎、抗病毒和趋化蛋白编码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通路中的二型性所介导的。综上所述，这些研究将全面分析类固醇激素和免疫调节蛋白基因如何相互作用，以影响对传染病表型反应的性别差异，并可能有助于开发治疗 出血热病毒在两性中都会成功。

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.