IAV NS1 carried by exosomes promotes IL-10 production by the PI3K-AKT-GSK3β-CREB pathway

Influenza A virus (IAV) has a potential pandemic threat and is a major challenge to human health. Interleukin-10 (IL-10) is a pleiotropic factor that can be induced by influenza infection and is closely associated with the development of pneumonia. However, the specific viral protein responsible for regulating IL-10 production during IAV infection, as well as its detailed mechanisms involved, remains incompletely understood. In this study, we screened the IAV genes and found that IAV Non-structural protein 1 (NS1) upregulates the production of IL-10 through the PI3K-AKT pathway. Moreover, we found that NS1 interacted with PI3K p85β subunit, leading to the activation of PI3K-AKT. This subsequently inhibits GSK3β, thereby promoting the phosphorylation and nuclear translocation of CREB, and ultimately inducing the expression of IL-10. Furthermore, IAV-infected A549-derived exosomes carrying NS1 promoted IL-10 by the same pathway. Together, these results suggest that IAV increased IL-10 expression through multiple pathways, including direct action of NS1 or through exosomes. Our findings provide novel insights into additional functionalities of IAV NS1 during infection.