An Endogenously activated antiviral state restricts SARS-CoV-2 infection in differentiated primary airway epithelial cells
An Endogenously activated antiviral state restricts SARS-CoV-2 infection in differentiated primary airway epithelial cells
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内源性激活的抗病毒状态限制分化的初级气道上皮细胞中的 SARS-CoV-2 感染
DOI：
10.1101/2021.08.17.456707
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Broadbent L
中科院分区：
文献类型：
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作者：
Broadbent L
严重急性呼吸系统综合征冠状病毒2型（SARS-CoV-2）是冠状病毒病-19（COVID-19）大流行的原因，于2019年底被发现，截至2022年2月已造成超过500万人死亡。迄今为止，针对COVID-19的靶向抗病毒干预措施有限。SARS-CoV-2感染的范围从无症状到致命疾病。然而，SARS-CoV-2感染的不同结果的原因尚未阐明。在这里，我们表明，内源性激活的干扰素λ（IFNλ1）途径导致对SARS-CoV-2感染的抵抗。使用来自多个成年供体的分化良好的原代鼻上皮细胞（WD-PNEC）培养模型，我们发现对SARS-CoV-2感染的易感性不同，但对呼吸道合胞病毒（RSV）感染的易感性不同。4例供体中有1例对SARS-CoV-2感染有抵抗力。高基线IFNλ1表达水平和相关的干扰素刺激基因与SARS-CoV-2感染的抗性相关。在具有高内源性IFNλ1分泌的WD-PNEC中抑制JAK/STAT途径导致较高的SARS-CoV-2滴度。相反，对感染易感的WD-PNEC进行预防性IFNλ治疗导致病毒滴度降低。内源性激活的IFNλ反应，可能是由于遗传差异，可能是人类对SARS-CoV-2感染易感性差异的一种解释。重要的是，我们的工作支持IFNλ作为抗SARS-CoV-2感染的潜在药物的继续探索。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the coronavirus disease-19 (COVID-19) pandemic, was identified in late 2019 and caused >5 million deaths by February 2022. To date, targeted antiviral interventions against COVID-19 are limited. The spectrum of SARS-CoV-2 infection ranges from asymptomatic to fatal disease. However, the reasons for varying outcomes to SARS-CoV-2 infection are yet to be elucidated. Here we show that an endogenously activated interferon lambda (IFNλ1) pathway leads to resistance against SARS-CoV-2 infection. Using a well-differentiated primary nasal epithelial cell (WD-PNEC) culture model derived from multiple adult donors, we discovered that susceptibility to SARS-CoV-2 infection, but not respiratory syncytial virus (RSV) infection, varied. One of four donors was resistant to SARS-CoV-2 infection. High baseline IFNλ1 expression levels and associated interferon stimulated genes correlated with resistance to SARS-CoV-2 infection. Inhibition of the JAK/STAT pathway in WD-PNECs with high endogenous IFNλ1 secretion resulted in higher SARS-CoV-2 titres. Conversely, prophylactic IFNλ treatment of WD-PNECs susceptible to infection resulted in reduced viral titres. An endogenously activated IFNλ response, possibly due to genetic differences, may be one explanation for the differences in susceptibility to SARS-CoV-2 infection in humans. Importantly, our work supports the continued exploration of IFNλ as a potential pharmaceutical against SARS-CoV-2 infection.