Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
Department of Pediatrics, Division of Infectious Diseases, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Nat Commun. 2022 Oct 29;13(1):6456. doi: 10.1038/s41467-022-34111-0.
Communicable respiratory viral infections pose both epidemic and pandemic threats and broad-spectrum antiviral strategies could improve preparedness for these events. 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). A top hit from our screen, beta-1,3-glucuronyltransferase 1 (B3GAT1), effectively blocks IBV infection. Subsequent studies reveal that B3GAT1 activity prevents cell surface sialic acid expression. 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. 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. Thus, B3GAT1 may represent a host-directed broad-spectrum antiviral target with utility against clinically relevant respiratory viruses.
传染性呼吸道病毒感染既构成了流行威胁，也构成了大流行威胁，广谱抗病毒策略可以提高对此类事件的准备。为了发现可能作为宿主定向抗病毒治疗开发合适靶点的宿主抗病毒限制因子，我们在这里用乙型流感病毒（IBV）进行了全基因组 CRISPR 激活筛选。我们的筛选中排名靠前的一个靶点是β-1,3-葡糖醛酸基转移酶 1（B3GAT1），它能有效阻止 IBV 感染。随后的研究表明，B3GAT1 活性阻止了细胞表面唾液酸的表达。由于这种作用机制，B3GAT1 表达广泛限制了需要唾液酸进入的病毒的感染，包括维多利亚和 Yamagata 谱系 IBV、H1N1/H3N2 流感 A 病毒（IAV）以及不相关的肠道病毒 D68。为了了解 B3GAT1 诱导作为体内抗病毒策略的潜在效用，我们在鼠呼吸道上皮细胞中特异性表达 B3GAT1，发现过度表达不仅耐受良好，还能保护雌性小鼠免受多种流感病毒的致命病毒攻击，包括具有大流行潜力的 H1N1 IAV。因此，B3GAT1 可能代表一种具有针对临床相关呼吸道病毒的用途的宿主定向广谱抗病毒靶点。
