Institute of Virology and Immunology, Bern, Switzerland.
Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
J Virol. 2022 Jun 8;96(11):e0036422. doi: 10.1128/jvi.00364-22. Epub 2022 May 19.
Effective broad-spectrum antivirals are critical to prevent and control emerging human coronavirus (hCoV) infections. Despite considerable progress made toward identifying and evaluating several synthetic broad-spectrum antivirals against hCoV infections, a narrow therapeutic window has limited their success. Enhancing the endogenous interferon (IFN) and IFN-stimulated gene (ISG) response is another antiviral strategy that has been known for decades. However, the side effects of pegylated type-I IFNs (IFN-Is) and the proinflammatory response detected after delayed IFN-I therapy have discouraged their clinical use. In contrast to IFN-Is, IFN-λ, a dominant IFN at the epithelial surface, has been shown to be less proinflammatory. Consequently, we evaluated the prophylactic and therapeutic efficacy of IFN-λ in hCoV-infected airway epithelial cells and mice. Human primary airway epithelial cells treated with a single dose of IFN-I (IFN-α) and IFN-λ showed similar ISG expression, whereas cells treated with two doses of IFN-λ expressed elevated levels of ISG compared to that of IFN-α-treated cells. Similarly, mice treated with two doses of IFN-λ were better protected than mice that received a single dose, and a combination of prophylactic and delayed therapeutic regimens completely protected mice from a lethal Middle East respiratory syndrome CoV (MERS-CoV) infection. A two-dose IFN-λ regimen significantly reduced lung viral titers and inflammatory cytokine levels with marked improvement in lung inflammation. Collectively, we identified an effective regimen for IFN-λ use and demonstrated the protective efficacy of IFN-λ in MERS-CoV-infected mice. Effective antiviral agents are urgently required to prevent and treat individuals infected with SARS-CoV-2 and other emerging viral infections. The COVID-19 pandemic has catapulted our efforts to identify, develop, and evaluate several antiviral agents. However, a narrow therapeutic window has limited the protective efficacy of several broad-spectrum and CoV-specific antivirals. IFN-λ is an antiviral agent of interest due to its ability to induce a robust endogenous antiviral state and low levels of inflammation. Here, we evaluated the protective efficacy and effective treatment regimen of IFN-λ in mice infected with a lethal dose of MERS-CoV. We show that while prophylactic and early therapeutic IFN-λ administration is protective, delayed treatment is detrimental. Notably, a combination of prophylactic and delayed therapeutic administration of IFN-λ protected mice from severe MERS. Our results highlight the prophylactic and therapeutic use of IFN-λ against lethal hCoV and likely other viral lung infections.
有效的广谱抗病毒药物对于预防和控制新兴的人类冠状病毒（hCoV）感染至关重要。尽管已经在鉴定和评估几种针对 hCoV 感染的合成广谱抗病毒药物方面取得了相当大的进展，但治疗窗口狭窄限制了它们的成功。增强内源性干扰素（IFN）和 IFN 刺激基因（ISG）反应是另一种抗病毒策略，这种策略已经存在了几十年。然而，聚乙二醇化的 I 型 IFNs（IFN-Is）的副作用以及 IFN-I 治疗后延迟产生的促炎反应阻碍了它们的临床应用。与 IFN-Is 不同，在上皮表面占主导地位的 IFN-λ 被证明炎症反应较小。因此，我们评估了 IFN-λ 在 hCoV 感染的气道上皮细胞和小鼠中的预防和治疗效果。用单剂量 IFN-I（IFN-α）和 IFN-λ 处理的人原代气道上皮细胞显示出相似的 ISG 表达，而用两剂量 IFN-λ 处理的细胞表达的 ISG 水平高于 IFN-α 处理的细胞。同样，用两剂量 IFN-λ 治疗的小鼠比用单剂量 IFN-λ 治疗的小鼠得到更好的保护，预防和延迟治疗方案的组合可完全保护小鼠免受致命的中东呼吸综合征冠状病毒（MERS-CoV）感染。两剂量 IFN-λ 方案可显著降低肺病毒滴度和炎症细胞因子水平，并显著改善肺部炎症。总的来说，我们确定了 IFN-λ 应用的有效方案，并证明了 IFN-λ 在 MERS-CoV 感染小鼠中的保护作用。急需有效的抗病毒药物来预防和治疗感染 SARS-CoV-2 和其他新兴病毒感染的个体。COVID-19 大流行推动了我们识别、开发和评估几种抗病毒药物的努力。然而，治疗窗口狭窄限制了几种广谱和 CoV 特异性抗病毒药物的保护效果。IFN-λ 是一种有前途的抗病毒药物，因为它能够诱导强大的内源性抗病毒状态和低水平的炎症。在这里，我们评估了 IFN-λ 在感染致死剂量 MERS-CoV 的小鼠中的保护效果和有效治疗方案。我们发现，虽然预防性和早期治疗性 IFN-λ 给药具有保护作用，但延迟治疗则有害。值得注意的是，预防性和延迟治疗性 IFN-λ 联合给药可保护小鼠免受严重的 MERS 感染。我们的结果强调了 IFN-λ 对致死性 hCoV 以及可能其他病毒性肺部感染的预防和治疗作用。
