Influenza infected macrophages release viral ribonucleoproteins that shape the local host response

Airway epithelial cells and macrophages (MΦ) represent cellular targets of infection by influenza A virus (IAV). Epithelial cells support IAV infection and replication by enabling the generation and release of new viral particles (productive replication). In contrast, MΦ are susceptible to initial IAV infection but the release of infectious viral particles is inhibited through abortive replication. Despite the lack of infectious virions released from infected MΦ, we detected newly synthesised viral RNA and nucleoprotein (NP) in MΦ supernatants. We show that viral RNA is released from infected MΦ as viral ribonucleoprotein (vRNP) complexes which elicits potent inflammatory responses when exposed to uninfected cells. These vRNPs specifically induced IL-1β, CXCL13, IL-32, CCL4 and CXCL10 in uninfected cells and were at least partially sensed through the RIG-I/MDA5 pathway. While MΦ represent a dead-end for IAV infection through abortive replication, the release of vRNPs shapes immune repsonses of uninfected cells in the local microenvironment. ### Competing Interest Statement The authors have declared no competing interest.