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），在没有细胞裂解的情况下，引起与血管通透性显著增加相关的疾病。安第斯山脉病毒（ANDV）感染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）。巨大的肺毛细血管床为ANDV感染提供了丰富的EC，并且EC的感染为ANDV增加毛细血管通透性和引起水肿提供了主要手段。ANDV感染响应于VEGF显著增强EC渗透性，并且在非致病性TULV感染或响应于TNF 1后未观察到这一点。我们最近的研究结果表明，ANDV感染的EC的结果在VEGFR 2的过度磷酸化，增加的VE-钙粘蛋白从AJs的解离和增加的细胞旁通透性。我们还表明ANDV诱导的渗透性被血管生成素-1（Ang-1）或鞘氨醇-1磷酸（S1 P）抑制，其拮抗VEGF指导的渗透性。这些发现表明ANDV诱导的水肿可能通过抑制VEGFR 2信号通路而被阻断。ANDV感染的叙利亚仓鼠是汉坦病毒病的唯一动物模型，它与HPS非常相似，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，并且由JayHooper开发，JayHooper是该提议的共同研究者。在与Jay Hooper的联合提案中，我们建议将我们对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屏障功能的化合物在叙利亚仓鼠中预防HPS样疾病的能力的功效。

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.