Cellular and Molecular Mediators of Hantavirus Infection

汉坦病毒感染的细胞和分子介质

• 批准号: 6605395
• 负责人: SABRA L. KLEIN
• 金额: $ 20.66万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6605395
• 关键词: Hantavirus; androgens; biological polymorphism; biological signal transduction; corticosteroid receptors; estrogens; gene expression; genetic transcription; hormone regulation /control mechanism; laboratory rat; nuclear factor kappa beta; protein structure function; virus infection mechanism

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.

汉坦病毒是人畜共患病原体，由多种啮齿动物宿主物种携带，具有地域多样性，可引起目前无法治愈的人类疾病。该提案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的易感性的机制，以开发适当的感染疗法。人类和几种啮齿动物宿主物种中汉坦病毒感染存在性别差异，其中雄性受感染的数量多于雌性。尽管汉坦病毒感染的性别差异可能反映了行为的二态性，例如啮齿类动物的攻击性或人类的职业性，但最近 我们实验室的数据表明，针对感染和病毒复制的免疫反应在性别之间存在差异。接种首尔病毒（即挪威大鼠体内天然存在的汉坦病毒）后，雄性大鼠表现出更高的抗体反应，通过更多途径传播病毒的时间更长，并且目标器官中存在更多的病毒RNA拷贝，例如 肺部比女性好。女性中抗病毒转录因子（例如 eIF-2α、NF-KappaB、IRF 和 STAT）的表达高于男性。转录因子的上调，例如与男性相比，女性中的 NF-KappaB 可能是编码促炎、趋化和抗病毒蛋白的基因表达升高的原因。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-KappaB 介导的信号转导的影响。该研究计划的主要目的是检验以下假设：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来介导首尔病毒感染中的性别差异。 该提案的目标将通过以下方式实现：1）表征感染急性期和持续期期间编码促炎、抗病毒和趋化蛋白的基因表达和翻译的性别差异； 2）在发育过程中的不同时间操纵性类固醇，以确定基因的表达和翻译是否 编码促炎、抗病毒和趋化蛋白，受性类固醇的影响； 3) 评估编码促炎蛋白、抗病毒蛋白和趋化蛋白的基因的表达和翻译是否存在性别差异 由糖皮质激素受体介导途径的二态性介导。总而言之，这些研究将全面分析类固醇激素和编码免疫调节蛋白的基因如何相互作用，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方法 出血热病毒对男女都会成功。