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Updated: Sep 26, 2025
Infection of Primary Nasal Epithelial Cells Grown at an Air-Liquid Interface to Characterize Human Coronavirus-Host Interactions
Published on: September 22, 2023
An endogenously activated antiviral state restricts SARS-CoV-2 infection in differentiated primary airway epithelial
Lindsay Broadbent1, Connor G G Bamford1, Guillermo Lopez Campos1
1Wellcome-Wolfson Institute for Experimental Medicine, Queens University Belfast, Belfast, Northern Ireland, United Kingdom.
Abstract:
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.
Insights
An endogenously activated interferon lambda 1 (IFNλ1) pathway confers resistance to SARS-CoV-2 infection. This finding suggests IFNλ1 may be a potential pharmaceutical target for COVID-19 treatment.
Area of Science:
- Immunology
- Virology
- Genetics
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, has resulted in millions of deaths globally.
- Limited antiviral interventions exist for COVID-19, and reasons for varied disease severity remain unclear.
Purpose of the Study:
- To investigate the role of endogenous interferon lambda 1 (IFNλ1) in SARS-CoV-2 infection resistance.
- To explore potential pharmaceutical applications of IFNλ1 for COVID-19.
Main Methods:
- Utilized well-differentiated primary nasal epithelial cell (WD-PNEC) cultures from multiple donors.
- Assessed SARS-CoV-2 and RSV susceptibility, IFNλ1 expression, and JAK/STAT pathway activity.
- Administered prophylactic IFNλ treatment and inhibited the JAK/STAT pathway.
Main Results:
- SARS-CoV-2 susceptibility varied among donors, unlike RSV susceptibility.
- High baseline IFNλ1 expression correlated with resistance to SARS-CoV-2.
- JAK/STAT pathway inhibition increased SARS-CoV-2 viral load, while IFNλ treatment reduced it.
Conclusions:
- Endogenously activated IFNλ1 pathway contributes to SARS-CoV-2 resistance, potentially due to genetic variations.
- IFNλ represents a promising therapeutic avenue for managing SARS-CoV-2 infections.
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