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（ECs），在没有细胞溶解的情况下，导致与血管通透性急剧增加相关的疾病。安第斯病毒（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）。广阔的肺毛细血管床为ANDV感染提供了丰富的内皮细胞，内皮细胞感染是ANDV增加毛细血管通透性和引起水肿的主要手段。ANDV感染显著增强EC对VEGF的通透性，而这在非致病性TULV感染或对TNF1的反应中没有观察到。我们最近的研究结果表明，ANDV感染ECs导致VEGFR2的过度磷酸化，ve -钙粘蛋白与AJs的分离增加，细胞旁通透性增加。我们还表明，血管生成素-1 （Ang-1）或鞘氨醇-1磷酸（S1P）可以抑制ANDV诱导的通透性，它们可以拮抗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信号通路而被阻断。ANDV感染叙利亚仓鼠是汉坦病毒病的唯一动物模型，与HPS非常相似，可导致致命性急性肺水肿。该模型允许研究针对ANDV疾病的潜在治疗化合物，并由本提案的共同研究者Jay Hooper开发。在与Jay Hooper的联合提案中，我们建议将我们对ANDV诱导的EC通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.