The GDF6-FTO axis modulates the innate immune and inflammatory response to human respiratory syncytial virus.

Respiratory syncytial virus (RSV) is one of the most common respiratory pathogens, causing a significant disease burden in young children and the elderly. Up to now, there is no specific drug in the clinic. N6-methyladenosine (mA) is a ubiquitous RNA modification in eukaryotes that regulates disease processes caused by viral infections. We here find that the depletion of the demethylase FTO stabilizes the mRNA of growth differentiation factor (GDF6), enhances the levels of type I interferon (I-IFN), and reduces the expression of pro-inflammatory factors, thereby exerting an antiviral effect. Furthermore, a deficiency in the binding protein IGF2BP1 results in decreased GDF6 expression, which in turn reduces I-IFN production. We further demonstrated changes in mA levels in RSV-infected throat swabs. In summary, we have demonstrated that RSV infection induces changes in host mA modifications, and FTO-mediated mA modifications ensure antiviral immunity by promoting the stability and protein translation of GDF6 mRNA.