Therapeutic Interventions Against ANDV Induced Pathogenesis

描述（由申请人提供）：汉坦病毒主要感染内皮细胞（EC），并且在没有细胞裂解的情况下，引起与血管通透性急剧增加相关的疾病。安第斯病毒 (ANDV) 感染会导致急性肺水肿和呼吸功能不全，称为汉坦病毒肺综合征 (HPS)。广阔的肺毛细血管床为ANDV感染提供了丰富的EC，EC的感染为ANDV增加毛细血管通透性并引起水肿提供了主要手段。 ANDV 感染可显着增强 EC 对 VEGF 的通透性，而在非致病性 TULV 感染或对 TNF1 的反应中未观察到这一点。我们最近的研究结果表明，ANDV 感染 EC 会导致 VEGFR2 过度磷酸化、VE-钙粘蛋白与 AJ 的解离增加以及细胞旁通透性增加。我们还表明，ANDV 诱导的通透性受到血管生成素-1 (Ang-1) 或磷酸鞘氨醇-1 (S1P) 的抑制，它们拮抗 VEGF 引导的通透性。这些发现表明 ANDV 诱导的水肿可能通过抑制 VEGFR2 信号通路来阻断。叙利亚仓鼠的 ANDV 感染是唯一一种与 HPS 非常相似的汉坦病毒病动物模型，可导致致命的急性肺水肿。该模型允许研究针对 ANDV 疾病的潜在治疗化合物，由该提案的联合研究员 Jay Hooper 开发。在与 Jay Hooper 的联合提案中，我们建议将对 ANDV 诱导的 EC 渗透性的基本理解应用于汉坦病毒病的叙利亚仓鼠模型。在这里，我们将评估增强 EC 屏障功能的化合物预防叙利亚仓鼠 HPS 样疾病的功效。

DESCRIPTION (provided by applicant): Hantaviruses predominantly infect endothelial cells (ECs), and in the absence of cell lysis, cause diseases associated with dramatic increases in vascular permeability. Andes virus (ANDV) infection results in acute pulmonary edema and respiratory insufficiency termed hantavirus pulmonary syndrome (HPS). Vast pulmonary capillary beds provide an abundance of ECs for ANDV to infect and infection of ECs provides a primary means for ANDV to increase capillary permeability and cause edema. ANDV infection dramatically enhances EC permeability in response to VEGF and this is not observed following infection by non-pathogenic TULV or in response to TNF1. Our recent findings indicate that ANDV infection of ECs results in the hyperphosphorylation of VEGFR2, increased dissociation of VE-cadherin from AJs and increased paracellular permeability. We have also shown that ANDV induced permeability is inhibited by angiopoietin-1 (Ang-1), or sphingosine-1 phosphate (S1P) which antagonize VEGF directed permeability. These findings suggest that ANDV induced edema may be blocked by inhibiting VEGFR2 signaling pathways. ANDV infection of Syrian hamsters is the only animal model of hantavirus disease which closely mimics HPS, resulting in fatal acute pulmonary edema. This model permits the study of potential therapeutic compounds against ANDV disease and was developed by Jay Hooper the co- investigator on this proposal. In this joint proposal with Jay Hooper, we propose to apply our basic understanding of ANDV induced EC permeability to the Syrian Hamster model of hantavirus disease. Here we will evaluate the efficacy of compounds that enhance EC barrier functions for their ability to prevent HPS-like disease in Syrian hamsters.