An endogenously activated antiviral state restricts SARS-CoV-2 infection in differentiated primary airway epithelial cells

Lindsay Broadbent*, Connor G G Bamford, Guillermo Lopez Campos, Sheerien Manzoor, David Courtney, Ahlam Ali, Olivier Touzelet, Conall McCaughey, Ken Mills, Ultan F Power*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish
Article numbere0266412
JournalPLoS ONE
Issue number4
Publication statusPublished - 18 Apr 2022


  • Antiviral Agents/pharmacology
  • COVID-19
  • Epithelial Cells/metabolism
  • Humans
  • Interferons/metabolism
  • Janus Kinases/metabolism
  • Respiratory Syncytial Virus Infections
  • SARS-CoV-2
  • STAT Transcription Factors/metabolism
  • Signal Transduction


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