Role of Reactive Oxygen Species in Nipah Virus Pathogenesis

描述（由研究者提供）：在这里，我们试图研究活性氧（ROS）在尼帕病毒（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，作为治疗干预策略的目标，以预防和治疗致命的NiV感染。本研究的目的是利用人类呼吸道的新型和生理相关的体外和体内模型来确定NiV发病机制的关键介质。我们的中心假设是，NiV感染人呼吸道上皮导致ROS的产生，向关键的促炎介质发出信号，并导致免疫细胞的募集。这项研究的基本原理是，一旦我们确认了ROS在亨尼帕病毒发病机制中的作用，我们就可以利用这些靶点开发新的治疗干预策略来治疗和预防致命疾病。我们计划通过以下两个具体目标来检验我们的中心假设：1。利用我们新建立的人原代气道上皮细胞NiV感染模型确定ROS诱导的功能作用。利用一种新的人源化小鼠模型验证人呼吸道上皮在niv诱导的细胞募集中的体内作用。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迁移很重要，并测试抗氧化剂处理是否会导致这些细胞因子/趋化因子水平的降低和免疫细胞的募集。在第二个目标下，我们将利用人类肺异种移植的新型人源化小鼠模型，确定在NiV感染后，哪些细胞被募集到人类肺中，确认该模型中ROS的诱导，并测试抗氧化处理的效果。这种方法是创新的，因为它使用了人类呼吸道的新颖和生物学相关模型来关注亨尼帕病毒发病机制的早期步骤。提出的研究是重要的，因为这些模型的可用性来研究亨尼帕病毒的发病机制，预计将导致鉴定宿主和病毒因素对人类感染亨尼帕病毒后的致命结果至关重要。

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.