Core Viewpoint - The article discusses the significant role of respiratory viruses, particularly coronaviruses and influenza viruses, in global pandemics and their impact on public health, emphasizing the importance of understanding immune responses and potential antiviral strategies [1][2]. Group 1: Immune Response and Interferon - The innate immune response, including interferons (IFN) and interferon-stimulated genes (ISG), serves as the first line of defense against viral attacks [2]. - Delayed or impaired type I interferon (IFN-I) responses are notable characteristics of severe COVID-19 and influenza infections, with 3.5% of life-threatening COVID-19 patients exhibiting harmful mutations in interferon system genes [2]. - In critical COVID-19 patients, nearly 15% have been found to possess neutralizing antibodies against their own interferons, indicating a significant immune response issue [2]. Group 2: GALNT2 and Antiviral Mechanism - A recent study published in Nature Microbiology identifies GALNT2 as an ISG with broad antiviral activity, establishing it as a crucial defense factor against respiratory virus infections [3][9]. - GALNT2 inhibits the replication of various coronaviruses and influenza viruses, promoting viral clearance and reducing disease severity through O-glycosylation of viral proteins [6][9]. - The mechanism involves GALNT2 modifying the spike protein of SARS-CoV-2, preventing its cleavage by proteases, thus blocking virus-host cell fusion [6][7]. Group 3: Genetic Insights and Implications - Analysis of human genetic data reveals that individuals with GALNT2 gene mutations that impair antiviral function have a significantly higher risk of hospitalization after SARS-CoV-2 infection [8]. - The findings deepen the understanding of host-virus interactions and provide new targets for developing broad-spectrum antiviral strategies against respiratory pathogens [10].