A novel interferon stimulated gene GALNT2 is required to restrict respiratory virus infections

Respiratory viruses, particularly coronaviruses (CoVs) and influenza A viruses (IAVs), have driven global pandemics, with zoonotic spillover posing ongoing threats to public health. SARS-CoV-2, the cause of COVID-19, emerged in 2019, devastating global health and claiming over 7 million lives, while the 2009 influenza pandemic caused at least 200,000 deaths. The innate immune system serves as the first line of defense, where type I interferons (IFNs) and interferon-stimulated genes (ISGs) play pivotal antiviral roles. Impaired IFN-I responses are linked to severe COVID-19 and influenza, underscoring their importance: life-threatening COVID-19 cases often involve genetic defects in IFN pathways or neutralizing autoantibodies that dampen IFN activity, whereas children’s resilience to severe infection correlates with robust IFN responses. Recombinant IFNs show therapeutic potential, though timing is critical. Key ISGs like OAS1 and OASL further illustrate IFN-mediated protection, highlighting the need to dissect how individual ISGs aid viral clearance and mitigate disease. In this context, we identified GALNT2, an O-GalNAc transferase, as a novel ISG that enhances viral clearance and reduces susceptibility and severity in both SARS-CoV-2 and IAV infections.