Type I and Type III Interferons Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures

J Virol. 2020 Sep 15;94(19):e00985-20. doi: 10.1128/JVI.00985-20. Print 2020 Sep 15.

Abstract

The newly emerged human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a pandemic of respiratory illness. Current evidence suggests that severe cases of SARS-CoV-2 are associated with a dysregulated immune response. However, little is known about how the innate immune system responds to SARS-CoV-2. In this study, we modeled SARS-CoV-2 infection using primary human airway epithelial (pHAE) cultures, which are maintained in an air-liquid interface. We found that SARS-CoV-2 infects and replicates in pHAE cultures and is directionally released on the apical, but not basolateral, surface. Transcriptional profiling studies found that infected pHAE cultures had a molecular signature dominated by proinflammatory cytokines and chemokine induction, including interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and CXCL8, and identified NF-κB and ATF-4 as key drivers of this proinflammatory cytokine response. Surprisingly, we observed a complete lack of a type I or III interferon (IFN) response to SARS-CoV-2 infection. However, pretreatment and posttreatment with type I and III IFNs significantly reduced virus replication in pHAE cultures that correlated with upregulation of antiviral effector genes. Combined, our findings demonstrate that SARS-CoV-2 does not trigger an IFN response but is sensitive to the effects of type I and III IFNs. Our studies demonstrate the utility of pHAE cultures to model SARS-CoV-2 infection and that both type I and III IFNs can serve as therapeutic options to treat COVID-19 patients.IMPORTANCE The current pandemic of respiratory illness, COVID-19, is caused by a recently emerged coronavirus named SARS-CoV-2. This virus infects airway and lung cells causing fever, dry cough, and shortness of breath. Severe cases of COVID-19 can result in lung damage, low blood oxygen levels, and even death. As there are currently no vaccines approved for use in humans, studies of the mechanisms of SARS-CoV-2 infection are urgently needed. Our research identifies an excellent system to model SARS-CoV-2 infection of the human airways that can be used to test various treatments. Analysis of infection in this model system found that human airway epithelial cell cultures induce a strong proinflammatory cytokine response yet block the production of type I and III IFNs to SARS-CoV-2. However, treatment of airway cultures with the immune molecules type I or type III interferon (IFN) was able to inhibit SARS-CoV-2 infection. Thus, our model system identified type I or type III IFN as potential antiviral treatments for COVID-19 patients.

Keywords: COVID-19; SARS-CoV-2; cytokines; innate immunity; lung; type I interferon.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Betacoronavirus / immunology*
  • Betacoronavirus / physiology
  • Bronchi / cytology
  • Bronchi / immunology
  • Bronchi / virology
  • COVID-19
  • Cell Line
  • Cells, Cultured
  • Chemokines / immunology
  • Chlorocebus aethiops
  • Coronavirus Infections / immunology*
  • Coronavirus Infections / virology
  • Cytokines / immunology
  • Dogs
  • Epithelial Cells / immunology*
  • Epithelial Cells / virology
  • Humans
  • Interferon Type I / immunology*
  • Interferons / immunology*
  • Lung / cytology
  • Lung / immunology
  • Lung / virology
  • Madin Darby Canine Kidney Cells
  • Pandemics
  • Pneumonia, Viral / immunology*
  • Pneumonia, Viral / virology
  • SARS-CoV-2
  • Vero Cells
  • Virus Replication

Substances

  • Chemokines
  • Cytokines
  • Interferon Type I
  • interferon type III
  • Interferons