Additionally, emerging respiratory viruses with unknown correlates of protection can require significant lead times before protective vaccines can be developed and distributed 7. While vaccination is generally considered the best strategy to prevent such infections, many known viral strains still lack effective vaccination strategies 5, 6. Further, the aerosol transmission of respiratory infections has facilitated global pandemics with influenza A viruses (IAVs) and coronaviruses and the threat of future pandemics from a variant of these (or currently unknown) viruses remains a source of concern 3, 4. Respiratory viral infections present a major burden to public health and result in significant morbidity and mortality in the global population annually 1, 2. Thus, B3GAT1 may represent a host-directed broad-spectrum antiviral target with utility against clinically relevant respiratory viruses. To understand the potential utility of B3GAT1 induction as an antiviral strategy in vivo, we specifically express B3GAT1 in the murine respiratory epithelium and find that overexpression is not only well-tolerated, but also protects female mice from a lethal viral challenge with multiple influenza viruses, including a pandemic-like H1N1 IAV. Due to this mechanism of action, B3GAT1 expression broadly restricts infection with viruses that require sialic acid for entry, including Victoria and Yamagata lineage IBVs, H1N1/H3N2 influenza A viruses (IAVs), and the unrelated enterovirus D68.
Subsequent studies reveal that B3GAT1 activity prevents cell surface sialic acid expression. A top hit from our screen, beta-1,3-glucuronyltransferase 1 (B3GAT1), effectively blocks IBV infection. To discover host antiviral restriction factors that may act as suitable targets for the development of host-directed antiviral therapies, we here conduct a whole-genome CRISPR activation screen with influenza B virus (IBV). Communicable respiratory viral infections pose both epidemic and pandemic threats and broad-spectrum antiviral strategies could improve preparedness for these events.
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