In vitro and in vivo studies of GAPLINC identify it as a critical host factor involved in the regulation of influenza A virus infection

Abstract Although previous studies have suggested a role for GAPLINC in regulating influenza A virus (IAV) infection, the functional involvement of GAPLINC in IAV infection in vitro and in vivo 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. During IAV infection, activation of NF-κB and the downstream IL-6/STAT3 signaling pathway contribute, at least in part, to the downregulation of GAPLINC expression. 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 viral load and lung injury, slower body weight loss, and improved 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. Together, the results support the conclusion that GAPLINC plays a critical role in enhancing the pathogenesis of IAV, at least by targeting the IRF3 and ATG7-mediated autophagy pathway.