Therapeutic Interventions Against ANDV Induced Pathogenesis

描述(申请人提供)：汉坦病毒主要感染内皮细胞(ECs)，在没有细胞裂解的情况下，会导致与血管通透性急剧增加相关的疾病。安第斯病毒(Andes Virus，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感染提供了丰富的内皮细胞，而内皮细胞的感染为ANDV增加毛细血管通透性和引起水肿提供了主要手段。ANDV感染显著增强了内皮细胞对血管内皮生长因子的通透性，而在感染非致病性TULV或对TNF1的反应中没有观察到这一点。我们最近的发现表明，ANDV感染内皮细胞导致VEGFR2过度磷酸化，VE-钙粘蛋白从AJ解离增加，细胞旁通透性增加。我们还发现ANDV诱导的通透性可被血管生成素-1(Ang-1)或鞘氨醇-1-磷酸(S1P)抑制，后者可拮抗血管内皮生长因子诱导的通透性。这些结果表明，ANDV诱导的水肿可能通过抑制VEGFR2信号通路而被阻断。叙利亚仓鼠的ANDV感染是汉坦病毒病唯一的动物模型，它与HPS非常相似，导致致命的急性肺水肿。这个模型允许研究潜在的治疗ANDV疾病的化合物，并由Jay Hooper开发，他是这项提议的共同调查者。在这项与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到汉坦病毒病的叙利亚仓鼠模型中。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样病的能力的有效性。

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.