Pre-existing atopy prevents mortality from respiratory viral infection via induction of neuregulin-1

Abstract

Abstract Respiratory viral infections are associated with significant morbidity and mortality. RNA viruses, such as Respiratory Syncytial Virus (RSV) have been implicated in the development of asthma. We have a high-fidelity model of respiratory viral infection. Our mouse model utilizes a natural rodent pathogen, Sendai virus (SeV) similar to RSV, which faithfully replicates in mouse airway epithelial cells. We have shown that making these mice atopic (i.e, sensitized and challenged with house dust mite extracts) before viral infection prevents development of disease and more importantly prevents mice from dying of a normally lethal dose of SeV. Further, lungs and bronchoalveolar lavage fluid of atopic mice have significant increased levels of Neuregulin-1 (NRG1), potentially due to high expression of Nrg1 in dendritic cells as determined by RNAseq of CD11c+ cells. To determine a temporal relationship between NRG1 expression and respiratory viral infection, we utilized an in vitro system of well-differentiated human bronchial epithelial cells and mouse tracheal epithelial cells. Cells were treated on the basolateral side with NRG1 (10 to 100ng) for six-days before 4000 pfu of RSV-GFP or SeV-GFP inoculation, respectively. There was marked reduction in viral spreading (quantified by reduced GFP expression) with NRG1 treatment. Interleukin-6 (IL6) expression was reduced in NRG1 treated cells at 48h PI, as well. IL6 has been implicated with cellular stress and is involved in disease pathology. Therefore, reducing IL6 might affect the clinical presentation of serious infections. In conclusion our studies show that atopy induced NRG1 plays a novel role with a therapeutic potential in severe respiratory viral infections. Supported by Abigail Wexner Research Institute at Nationwide Children’s Hospital, Start-up fund to MHG