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.
The proposed research is relevant to the public health because the development of models of NiV infection in the human respiratory tract is ultimately expected to increase understanding of the pathogenesis of this virus, as well as identify targets for therapeutic intervention. Thus, the proposed research is relevant to the part of the NIAID's mission to better understand, treat and ultimately prevent infectious diseases.
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