In vitro and in vivo studies of GAPLINC identify it as a critical host factor enhancing the pathogenesis of Influenza A Virus

Although previous studies establish a role for GAPLINC in regulating influenza A virus (IAV) infection, functional involvement of GAPLINC in IAV pathogenesis remains largely unknown. Here, we found that expression of lncRNA GAPLINC is significantly downregulated by infections with several strains of IAV, including PR8, WSN, H3N2 and H9N2. Interestingly, infections with several other viruses, such as pseudorabies virus (PRV), Sendai virus (SeV), and Herpes simplex virus (HSV), also result in a significant reduction in GAPLINC expression. Additionally, we observed that IL-6 or activated STAT3 induces downregulation of GAPLINC, suggesting that suppression of GAPLINC expression by viral infection is regulated through the IL-6/STAT3 signaling pathway. Knockdown of GAPLINC in host cells impairs the viral replication, whereas overexpression of GAPLINC increases the viral titers. Both heterozygous GAPLINC knockout (KO) mice (GAPLINC+/-) and homozygous GAPLINC KO mice (GAPLINC-/-) were further employed to determine its function in vivo. GAPLINC knockout renders mice more resistant to IAV infection than wild type counterparts, as evidenced by lower degrees of viral load and lung injury, slower body weight loss, and better survival. We confirmed that GAPLINC obviously suppresses the IRF3 activation in IAV-infected cells. Moreover, we noticed that inhibition of ATG7-involved autophagy weakens the pro-viral activity of GAPLINC. Taken together, the results support that GAPLINC plays a critical role in enhancing the pathogenesis of IAV, at least by targeting the IRF3 and ATG7-mediated autophagy pathway.