Pre-Existing Atopy and Respiratory Viral Infections - Abstract Respiratory syncytial virus (RSV) infection leads to 2.1 million outpatient visits and 58,000 hospitalizations for children under 5 years of age. In those 65 years of age or older, RSV accounts for an average of 177,000 hospitalizations and 14,000 deaths annually, with similar mortality rates to influenza. Human data suggest pre- existing atopy may have a protective effect on mortality and severity of influenza and SARS-CoV-2 infection, and mouse models have shown protection from influenza mediated mortality with pre-existing atopy; however, the mechanism of this protection remains unclear. Using the house dust mite model of atopy, we found being atopic before infection with mouse parainfluenza virus type-1 (Sendai virus; SeV, a murine virus closely related to RSV), prevented mortality to an otherwise lethal viral dose. This survival depended upon CD11c+ cells, which produced neureglin-1 (NRG1). NRG1 appears to protect airway epithelium from the viral insult. Two alarmins released in the house dust mite model, IL33 and TSLP, induced NRG1 production from CD11c+ cells. CD11c+ cells from atopic mice or exogenous NRG1 reduced viral replication in airway epithelial cells in vitro and NRG1 significantly reduced mortality in vivo. Based on our data, we propose the hypothesis that pre-existing atopy protects against respiratory viral induced mortality in an IL33-TSLP dependent process that drives CD11c+ cells to produce NRG1, which restores epithelial cell homeostasis and protects epithelial cells from viral infection. Using our mouse model and mouse and human airway epithelial cell cultures to test these hypotheses, we propose to: (I) Define the NRG1 producing cell(s) in atopic mice and determine the requirement for NRG1 in atopy mediated survival from normally lethal SeV infection. (II) Determine the effect of NRG1 on epithelial cell function and protection from a respiratory viral insult. Upon completion of this proposal, we will have identified and characterized the NRG1 producing cells in the atopic mouse lung, the requirement for these cells and NRG1 in mediating survival in SeV infected atopic mice, and the requirement for alarmins in the development of the NRG1 producing cells and subsequent survival from the viral infection. In addition, we will have mechanistically characterized the effect of NRG1 on epithelial cells and determined the potential for NRG1 as a therapeutic agent. These findings form the basis for future studies to explore therapeutic interventions to prevent mortality from respiratory viral infections, with great potential to change medical care for severe respiratory viral infections.
