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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301783 | GEO | 2025/11/22

REPOSITORIES: GEO

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Project description:Inflammation following SARS-CoV-2 infection is a hallmark of COVID-19 and predictive of morbidity and death. However, the inflammatory pathways contributing to host-defense vs immune-mediated pathology have not been fully elucidated. This duality is clearly seen with type-I interferons (IFN-I) which are critical mediators of innate control of viral infections, but also drive recruitment of inflammatory cells to site of infection, a key feature of severe COVID-19. Here, we modulated IFN-I signaling in rhesus macaques (Macaca mulatta) prior to and during acute SARS-CoV-2 infection (day -1 through day 2 post infection) using a mutated IFNα2 (IFN-modulator; IFNmod) which blocks binding to IFNAR2 and signaling of endogenous IFN-I. IFNmod treatment resulted in a highly significant and consistent reduction in SARS-CoV-2 viral load in BAL, lung, and hilar LN (>3-log difference) and upper airways (nasal swabs). IFNmod also potently reduced inflammatory cytokines and chemokines in BAL, expansion of inflammatory monocytes (CD14+CD16+), and lung pathogenesis. Furthermore, Siglec-1 expression, which has been shown to enhance SARS-CoV-2 infection, was rapidly downregulated in the lung and on monocytes of IFNmod-treated SARS-CoV-2 infected RMs. Notably, while RNAseq analysis showed that IFNmod induced a modest upregulation of antiviral IFN-stimulated genes (ISGs) in uninfected RMs, it resulted in a robust reduction in pathways associated with both antiviral and inflammatory ISGs in SARS-CoV-2-infected RMs. In conclusion, IFNmod treatment provides sufficient levels of type I IFN signaling that inhibit viral replication while also limiting hyperinflammation. IFN-I plays a vital role in regulating SARS-CoV-2 replication, but uncontrolled IFN signaling has a detrimental impact on inflammation and pathogenesis. A better understanding of the role of IFN-I pathways is essential for designing therapies targeting these pathways and aimed at limiting COVID-19 pathogenesis.

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

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