HANTAVIRUS CELL INTERACTIONS

描述：(改编自调查人员的摘要)汉坦病毒是 人类两种高致命性疾病的病因：肾综合征出血热 (HFRS)和汉坦病毒肺综合征(HPS)。然而，隐含的意义 汉坦病毒的发病机制尚未确定，目前还没有动物 汉坦病毒病模型。我们最近确定字母ubeta3和 AlphaIIbbeta3整合素是病原体的细胞受体，但不是 非致病性汉坦病毒，这一发现与汉坦病毒直接相关 疾病到使用关键的黏附整合素在血小板和血管内皮细胞上。 此外，人类而不是小鼠的Beta3亚基使细胞对 由致病的汉坦病毒感染。这允许我们定义以下元素 汉坦病毒相互作用所需的β3整合素，并提出 用于汉坦病毒模型的人-β3转基因小鼠的研制 传染性和致病机制。β3整合素缺陷基因敲除小鼠 最近被证明模仿一种人类出血性疾病，Glanzmanns 血栓减少，并有明显的血管出血和血小板缺陷 聚合。我们已经证明了细胞对HPS的敏感性-和 引起肾综合征出血热的汉坦病毒是由人β3整合素产生的。有趣的是， 人而不是鼠的Beta3整合素允许汉坦病毒感染，这是 与实验小鼠(肌肉小鼠)不是汉坦病毒的事实一致 主持人。尽管关于β3整合素的天然来源知之甚少 宿主的研究结果表明，β3亚基足以决定 细胞对致病性汉坦病毒的易感性。β3整合素的作用 在血小板和内皮细胞功能方面，汉坦病毒病的性质和 只有致病性汉坦病毒才使用β3整合素，这表明 汉坦病毒与受体的相互作用在汉坦病毒中发挥核心作用 发病机制。我们将研究致病性汉坦病毒与 β3整合素受体，并建立人β3整合素转基因小鼠 作为汉坦病毒感染性和致病机制的潜在模型。这项建议 将定义汉坦病毒附着的整合素特定要求，并 汉坦病毒感染性的抑制剂与治疗和预防用途。 汉坦病毒致病动物模型的建立 建议广泛适用于汉坦病毒病、治疗学的研究 和保护性豁免权。具体目标：1)Beta3整合素要求 汉坦病毒感染性；2)阻断β3整合素与汉坦病毒的相互作用； 3)汉坦病毒感染及致病机制的转基因模型。

DESCRIPTION: (Adapted from the Investigator's abstract) Hantaviruses are the cause of 2 highly lethal human diseases: Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). However, mehanisms of hantavirus pathogenesis have not been defined and currently there is no animal model of hantavirus disease. We have recently determined that alphanubeta3 and alphaIIbbeta3 integrins are cellular receptors for pathogenic, but not non-pathogenic, hantaviruses and this finding directly relates hantavirus disease to the use of key adhesive integrins on platelet and endotheial cells. Further, human but not murine beta3 subunits render cells susceptible to infection by pathogenic hantaviruses. This permits us to define elements of beta3 integrins required for hantavirus interaction and to propose the development of human-beta3 transgenic mice for use as models of hantavirus infectivity and pathogenesis. beta3 integrin deficient knockout mice have recently been shown to mimic a human bleeding disorder, Glanzmanns thrombasthenia, and have marked vascular hemorrhage and defects in platelet aggregation. We have shown that cellular susceptibility to HPS- and HFRS-causing hantaviruses is confered by human beta3 integrins. Interestingly, human but not murine beta3 integrins permit hantavirus infection and this is consistent with the fact that laboratory mice (MUS musculis) are not hantavirus hosts. Although there is little known about beta3 integrins from their natural hosts, the findings demonstrate that beta3 subunits are sufficient to determine cellular susceptibility to pathogenic hantaviruses. The role of beta3 integrins in platelet and endothelial cell function, the nature of hantavirus disease and the use of beta3 integrins by only pathogenic hantaviruses, suggests that hantavirus-receptor interactions play a central role in hantavirus pathogenesis. We will investigate the interaction of pathogenic hantavirus with beta3 integrin receptors, and develop human beta3 integrin transgenic mice as potential models of hantavirus infectivity and pathogenesis. This proposal will define integrin specific requirements for hantavirus attachment and inhibitors of hantavirus infectivity with therapeutic and prophylactic uses. Development of an animal model of hantavirus pathogenesis within this proposal is broadly applicable to studies of hantavirus disease, therapeutics and protective immunity. Specific Aims: 1) beta3 Integrin Requirements for Hantavirus Infectivity; 2) Blocking beta3 Integrin-Hantavirus Interactions; 3) Transgenic Model of Hantavirus Infection and Pathogenesis.