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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DOI：
10.1371/journal.pone.0266412
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Power, Ultan F.
中科院分区：
文献类型：
--
作者：
Broadbent, Lindsay;Bamford, Connor G. G.;Lopez Campos, Guillermo;Manzoor, Sheerien;Courtney, David;Ali, Ahlam;Touzelet, Olivier;McCaughey, Conall;Mills, Ken;Power, Ultan F.
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.
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影响因子：
28.3
作者：
Pfaender S;Mar KB;Michailidis E;Kratzel A;Boys IN;V'kovski P;Fan W;Kelly JN;Hirt D;Ebert N;Stalder H;Kleine-Weber H;Hoffmann M;Hoffmann HH;Saeed M;Dijkman R;Steinmann E;Wight-Carter M;McDougal MB;Hanners NW;Pöhlmann S;Gallagher T;Todt D;Zimmer G;Rice CM;Schoggins JW;Thiel V
通讯作者：
Thiel V
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1016/s2213-2600(20)30566-x
发表时间：
2021-05
期刊：
The Lancet. Respiratory medicine
影响因子：
--
作者：
Feld JJ;Kandel C;Biondi MJ;Kozak RA;Zahoor MA;Lemieux C;Borgia SM;Boggild AK;Powis J;McCready J;Tan DHS;Chan T;Coburn B;Kumar D;Humar A;Chan A;O'Neil B;Noureldin S;Booth J;Hong R;Smookler D;Aleyadeh W;Patel A;Barber B;Casey J;Hiebert R;Mistry H;Choong I;Hislop C;Santer DM;Lorne Tyrrell D;Glenn JS;Gehring AJ;Janssen HLA;Hansen BE
通讯作者：
Hansen BE
影响因子：
6.7
作者：
Pervolaraki, Kalliopi;Talemi, Soheil Rastgou;Boulant, Steeve
通讯作者：
Boulant, Steeve
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.