Neuregulin-1 prevents death from a normally lethal respiratory viral infection.

Respiratory infections with RNA viruses such as respiratory syncytial virus (RSV) and influenza lead to significant morbidity and mortality. Using a natural rodent pathogen, Sendai virus (SeV), which is similar to RSV, mice made atopic with house dust mite survived a normally lethal SeV infection. Since we previously demonstrated a critical role for CD11c+ cells in the immune axis linking SeV to post-viral airway disease we posited that some of the protection against lethal SeV infection could be due to CD11c+ cells from atopic mice. Therefore, we performed RNA-seq analysis of CD11c+ cells isolated from atopic and non-atopic (NA) mouse lungs. While there were several dysregulated genes, one gene product whose expression was increased several-fold in atopic CD11c+ cells was neuregulin-1(NRG1) whose protein was found to be markedly elevated in the lungs and bronchoalveolar lavage fluid of atopic mice. When NRG1 was administered to naïve (non-atopic) mice it protected them from death with both SeV and mouse adapted influenza A virus (IAV). Survival was associated with reduced alveolar epithelium permeability and reduced phosphorylation of mixed lineage kinase domain-like (MLKL) protein indicating inhibition of necroptosis. In conclusion, our data demonstrate a unique function of NRG1 in respiratory viral infections by reducing alveolar leak, inhibiting epithelial necroptosis, and promoting homeostatic regulation of airway epithelium, all of which associate with markedly reduced mortality to the respiratory viral insult.