Influenza virus strategies to regulate S1P-metabolizing enzymes and evade host innate immunity for robust viral replication

Abstract

Viral infection is a complex network of interactions involving the host defending itself against the virus and the virus attempting to subdue host defenses and utilize the cellular machinery to promote its replication. Similar to other viruses, influenza A virus (IAV) manipulates and modulates the host cell to maintain control and optimize the cell for viral replication. One of the central obstacles IAV must overcome to further its replication is the type I IFN innate immune response. We have previously shown that sphingosine 1-phosphate (S1P) lyase (SPL) enhances IKK[epsilon]-mediated type I IFN responses. Here, we show that the nonstructural protein 1 (NS1) of IAV counteracts the SPL-mediated antiviral response by inducing SPL degradation. SPL was ubiquitinated and downregulated upon IAV infection or NS1 expression, and SPL-enhanced IFN production was strikingly inhibited by IAV NS1. Another IAV type I IFN-evasion strategy IAV is viral hemagglutinin (HA) facilitating type I IFN receptor 1 (IFNAR1) degradation. Further defining this, we determined that a cellular protein, poly (ADP-ribose) polymerase 1 (PARP1), plays a critical role in mediating IAV HA-induced degradation of IFNAR1. Knockdown or inhibition of PARP1 rescued IFNAR1 levels during IAV infection or HA expression, and PARP1 was crucial for robust IAV replication, which was associated with regulation of the type I IFN receptor signaling pathway. We have also found that sphingosine kinase 2 (SK2) enhances IAV replication along with multiple host factors. IAV protein synthesis during infection was enhanced by transient overexpression of SK2, and SK2 activity affected p21 expression during IAV infection. IAV infection led to increased SK2 and activated SK2 protein expression, and MEK/ERK activation was found to be important for this increase. Overall, these studies further define IAV-host interactions and reveal novel processes used by IAV to promote its own replication.