Influenza A virus inhibits TET2 expression by endoribonuclease PA-X to attenuate type I interferon signaling and promote viral replication

Author summaryInfluenza A virus (IAV) severely risks public health and economic stability. The endoribonuclease PA-X of IAV can limit host gene expression to facilitate viral replication. The Ten-Eleven Translocation 2 (TET2)-mediated DNA demethylation, which promotes gene transcription, is essential for host hematopoiesis and immunity. Here, we report that host TET2 mRNA can be targeted by PA-X protein for degradation, resulting in reduced TET2 expression during IAV infection. Notably, loss of TET2 markedly enhances IAV replication. Our study further confirmed that TET2 is responsible for the demethylation and expression of STAT1, ISG15, ISG20, and IFIT5 genes, which belong to type I interferon signaling and contribute to anti-viral immune response. Additionally, we identified that STAT1 is a critical factor in response to TET2 in the anti-IAV signaling. Taken together, we demonstrated that IAV inhibits TET2 expression by PA-X to reduce STAT1 and ISG expression, leading to immune escape and enhanced viral replication. Our research can provide a novel target for therapeutics to inhibit IAV infection and reduce pathology. Influenza A virus (IAV) expresses several accessory proteins to limit host anti-viral restriction factors to facilitate viral replication. The Ten-Eleven Translocation 2 (TET2) is a methylcytosine dioxygenase that promotes DNA demethylation by catalyzing the oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), which plays a vital role in hematopoiesis and immunity. Here we report that TET2 is a host restriction factor that limits IAV replication. But IAV endoribonuclease PA-X is able to remove the replication restriction by binding to TET2 mRNA and driving TET2 mRNA degradation to reduce TET2 expression during infection. Genetic inactivation of TET2 markedly enhances IAV replication in vitro and in vivo. Mechanistically, we found that TET2 regulates demethylation and transcription of STAT1 and some interferon-stimulated genes (ISGs), including ISG15, ISG20, and IFIT5, so the loss of TET2 greatly impairs type I Interferon signaling. Furthermore, we confirmed that TET2-mediated demethylation of the STAT1 gene is critical for interferon anti-viral activity. Our study demonstrates that the host TET2 is essential to the innate immune response against IAV infection.