Cellular and Molecular Mediators of Hantavirus Infection

汉坦病毒感染的细胞和分子介质

• 批准号: 6796352
• 负责人: SABRA L. KLEIN
• 金额: $ 40.88万
• 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/6796352
• 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.

汉坦病毒是由广泛的啮齿动物宿主物种携带的人畜共患病原体，地理上多种多样，并引起目前无法治愈的人类疾病。本研究的主要目的是为了更好地阐明宿主对汉坦病毒感染反应的细胞和分子机制。由于美国疾病控制与预防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宿主物种中有记录，其中雄性感染比雌性多。虽然汉坦病毒感染的性别差异可能反映了行为的二态性，例如啮齿动物的攻击性或人类的职业，但最近