Single-cell RNA sequencing of hematopoietic and non-hematopoietic cells defines a distinct signature in atopic and NRG1 mouse lung

Respiratory viral infections cause significant mortality. Pre-existing atopy has demonstrated protection from virus-induced death. Atopic mice with house dust mite (HDM) extract survive normally lethal parainfluenza (Sendai virus, SeV) and influenza A (IAV) infection. Neuregulin-1 (NRG1), markedly elevated in airways of atopic mice, has been shown to significantly attenuate mortality to SeV and IAV in non-atopic mice. Hypothesizing that atopy and NRG1 mediate protection from death through similar mechanisms, we anazlyed single-cell RNA sequencing data from CD45+ (hematopoietic) and CD45- (structural) lung cells prior to infection. Both treatments reduced alveolar macrophages, lymphatic endothelial cells, airway smooth muscle cells, and pericytes, while increasing alveolar type 2 cells. However, atopy led to increased fibroblasts with reduced club cells compared to NRG1 treatment. Further, in the hematopoietic cell compartment, atopy drove an increase in more inflammatory cells than NRG1 and associated with significant upregulation of immune cell signaling pathways, something not seen with NRG1 administration. Moreover, NRG1 knockdown did not reverse the protection from virus-induced death in mice with pre-existing atopy. Taken together, these data strongly suggest that atopy and NRG1 mediate increased survival from a respiratory viral infection through disparate mechanisms.