HANTAVIRUS CELL INTERACTIONS

描述：（改编自研究者摘要）汉坦病毒是 引起两种高致命性人类疾病：肾综合征出血热 （HFRS）和汉坦病毒肺综合征（HPS）。然而， 汉坦病毒发病机制尚未确定，目前没有动物 汉坦病毒病模型。我们最近确定， α IIb β 3整合素是致病性的细胞受体，但不是 非致病性汉坦病毒，这一发现直接关系到汉坦病毒 这种疾病与血小板和内皮细胞上关键粘附整合素的使用有关。 此外，人β 3亚基而非鼠β 3亚基使细胞对 病原性汉坦病毒感染。这使我们能够定义 β 3整合素所需的汉他病毒相互作用，并提出了 人β 3转基因小鼠作为汉坦病毒模型的开发 传染性和致病性。β 3整联蛋白缺陷敲除小鼠具有 最近被证明类似于人类出血性疾病， 血栓无力，并有明显的血管出血和血小板缺陷， 聚合来我们已经表明，细胞对HPS的易感性-和 引起HFRS的汉坦病毒由人β 3整合素赋予。有趣的是， 人而非鼠β 3整联蛋白允许汉坦病毒感染， 这与实验室小鼠（MUS musculis）不是汉坦病毒的事实一致 hosts.尽管对β 3整合素从其天然的 宿主，研究结果表明，β 3亚基足以确定 细胞对致病性汉坦病毒的易感性。β 3整合素的作用 血小板和内皮细胞功能，汉坦病毒病的性质， β 3整联蛋白仅被致病性汉坦病毒使用，这表明， 汉他病毒-受体相互作用在汉他病毒中起着重要作用 发病机制我们将研究致病性汉坦病毒与 β 3整联蛋白 受体，并开发人β 3整合素转基因小鼠 作为汉坦病毒感染性和发病机制的潜在模型。这项建议 将定义汉坦病毒附着的整合素特异性要求， 具有治疗和预防用途的汉坦病毒感染性抑制剂。 汉坦病毒发病机制动物模型的建立 该建议广泛适用于汉坦病毒病的研究， 和保护性豁免权具体目的：1）β 3整联蛋白要求 2）阻断β 3整合素-汉坦病毒相互作用; 3)汉坦病毒感染转基因模型的建立及其致病机制的研究。

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.