Neuregulin-1 protects against respiratory viral induced mortality

Respiratory viral infections due to RNA viruses such as respiratory syncytial virus (RSV) and influenza lead to significant morbidity and mortality. Using a natural rodent pathogen similar to RSV, Sendai virus (SeV), we found that mice made atopic with house dust mite before viral infection all survived a normally lethal SeV infection. Moreover, adoptive transfer of CD11c+ cells from atopic mice delayed viral mortality. Neuregulin-1 (NRG1) message was highly expressed in CD11c+ cells from atopic mice and atopic lungs and bronchoalveolar lavage fluid had elevated levels of NRG1 protein. Administration of NRG1 protected non-atopic mice from death and associated with reduced alveolar epithelium permeability. Utilizing an in vitro system of well-differentiated human bronchial epithelial cells and mouse tracheal epithelial cells NRG1 reduced RSV and SeV titers. Expression of genes that play a role in airway epithelium integrity and stability were altered by NRG1; potentially regulating viral induced dysregulation of the epithelia and suggesting NRG1 mediated maintenance of homeostasis. In conclusion, our studies demonstrate atopy induced NRG1 likely plays a novel role in survival from severe respiratory viral infections and may have therapeutic value to prevent mortality from these infections. Significance Severe respiratory viral infections are associated with significant mortality in infants and the elderly; however, allergic disease can protect from these outcomes. This study identified a protein called neuregulin-1 (NRG1), produced by cells of the immune system in allergic mice, that provides a survival advantage against respiratory viral infection. NRG1 pretreatment in non-atopic mice infected with a lethal dose of a rodent RNA virus (Sendai virus), similar to human respiratory syncytial virus, significantly reduced death. Further, NRG1 pretreatment reduced viral replication in human and mouse airway epithelial cell cultures. These studies signify a potential therapeutic role of NRG1 in modulating the severity of respiratory viral infections. ### Competing Interest Statement MHG is the Editor-in-Chief of the Annals of Allergy, Asthma & Immunology, has served on advisory boards for AbbVie, GSK, and Merck, has stock options in Invirsa, Inc., has a Patent Cooperation Treaty application (PCT) serial no. PCT/US22/78494 by the United States Patent and Trademark Office on the use of Neuregulin for protection against respiratory viral infection, serves on the Board of Directors of the American Board of Allergy and Immunology, Asthma and Allergy Foundation of America (AAFA), where he is Chair of their Medical Scientific Council, and is a member of the American Lung Association Scientific Advisory Committee. SRAH has 1) Patent Cooperation Treaty application (PCT) serial no. PCT/US22/78494 by the United States Patent and Trademark Office on the use of Neuregulin for protection against respiratory viral infection. (2) Patent on mitochondria genome editing by CRISPR. All other authors declare no competing interest.