Role of Reactive Oxygen Species in Nipah Virus Pathogenesis

描述(由研究人员提供)：在这里，我们试图研究活性氧簇(ROS)在尼帕病毒(Nipah Virus，NIV)发病机制中的作用。长期目标是确定宿主基因和毒力决定因素，作为预防和治疗致命性新城疫感染的治疗干预策略的目标。这里的目的是使用新的和生理上相关的体外和体内人类呼吸道模型来识别新城疫发病的关键介质。我们的中心假设是，新城疫病毒感染人类呼吸道上皮，导致ROS的产生，向关键的促炎介质发出信号，并导致免疫细胞的招募。这项研究的基本原理是，一旦我们确认ROS在海尼帕病毒发病机制中的作用，我们就可以利用这些靶点来开发治疗和预防致命疾病的新的治疗干预策略。我们计划通过追求以下两个具体目标来验证我们的中心假设：1.使用我们新开发的人呼吸道上皮细胞新城疫病毒感染模型来确定ROS诱导的功能作用；2.通过使用新的人源化小鼠模型来验证人呼吸道上皮细胞在体内在新城疫病毒诱导的细胞募集中的作用。在第一个目标下，我们将确认在气液界面生长的原代人类呼吸道上皮细胞中ROS的诱导，确定哪些关键的炎症介质对免疫细胞的跨内皮细胞迁移至关重要，并测试抗氧化剂处理是否会导致这些细胞因子/趋化因子的水平降低和免疫细胞的募集。在第二个目标下，我们将使用一种新的人源化小鼠人肺移植模型来确定NIV感染后哪些细胞被招募到人肺，确认该模型中ROS的诱导，并测试抗氧化治疗的效果。这种方法是创新的，因为它使用了新的和生物相关的人类呼吸道模型，专注于埃尼帕病毒致病的早期步骤。这项拟议的研究具有重要意义，因为这些模型用于研究海尼帕病毒的发病机制有望导致识别对人类海尼帕病毒感染后的致死结果至关重要的宿主和病毒因素。

DESCRIPTION (provided by investigator): Here we seek to study the role of Reactive Oxygen Species (ROS) in Nipah virus (NiV)pathogenesis. The long-term goal to identify host genes and virulence determinants that will serve as targets for therapeutic intervention strategies to preven and treat lethal NiV infection. The objective here is to identify key mediators of NiV pathogenesis using novel and physiologically relevant in vitro and in vivo models of the human respiratory tract. Our central hypothesis is that NiV infection of human respiratory epithelium results in induction of ROS production, signaling key pro-inflammatory mediators and resulting in recruitment of immune cells. The rationale for the proposed research is that, once we confirm the role of ROS in henipavirus pathogenesis, we can use these targets for the development of novel therapeutic intervention strategies to treat and prevent lethal disease. We plan to test our central hypothesis by pursuing the following two specific aims: 1. Define the functional roles of ROS induction using our newly developed NiV infection model of primary human airway epithelial cells and 2. Validate the in vivo role of human respiratory epithelium in NiV-induced cellular recruitment by using a novel humanized mouse model. Under the first aim, we will confirm induction of ROS in primary human respiratory epithelial cells grown at an air-liquid interface, identify which key inflammatory mediators are important of transendothelial migration of immune cell and test whether treatment with antioxidants will result in a reduction of the levels of these cytokine/chemokines and recruitment of immune cells. Under the second aim we will determine what cells are recruited to the human lung following NiV infection using a novel humanized mouse model with human lung xenografts, confirm the induction of ROS in this model and test the effect of antioxidant treatment. The approach is innovative because it uses novel and biologically relevant models of the human respiratory tract to focus on the early steps in henipavirus pathogenesis. The proposed research is significant because the availability of these models to study henipavirus pathogenesis is expected to lead to the identification of host and virus factors critical for the lethal outcome following human henipavirus infection.