Type I and Type III interferons restrict SARS-CoV-2 infection of human airway epithelial cultures

Abigail Vanderheiden, Philipp Ralfs, Tatiana Chirkova, Amit A. Upadhyay, Matthew G. Zimmerman, Shamika Bedoya, Hadj Aoued, Gregory M. Tharp, Kathryn L. Pellegrini, Candela Manfredi, Eric Sorscher, Bernardo Mainou, Jenna L. Lobby, Jacob E. Kohlmeier, Anice C. Lowen, Pei Yong Shi, Vineet D. Menachery, Larry J. Anderson, Arash Grakoui, Steven E. BosingerMehul S. Suthar

Research output: Contribution to journalReview article

3 Scopus citations

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 airliquid 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.

Original languageEnglish (US)
Article numbere00985-20
JournalJournal of virology
Volume94
Issue number19
DOIs
StatePublished - Oct 2020

Keywords

  • COVID-19
  • Cytokines
  • Innate immunity
  • Lung
  • SARS-CoV-2
  • Type I interferon

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Vanderheiden, A., Ralfs, P., Chirkova, T., Upadhyay, A. A., Zimmerman, M. G., Bedoya, S., Aoued, H., Tharp, G. M., Pellegrini, K. L., Manfredi, C., Sorscher, E., Mainou, B., Lobby, J. L., Kohlmeier, J. E., Lowen, A. C., Shi, P. Y., Menachery, V. D., Anderson, L. J., Grakoui, A., ... Suthar, M. S. (2020). Type I and Type III interferons restrict SARS-CoV-2 infection of human airway epithelial cultures. Journal of virology, 94(19), [e00985-20]. https://doi.org/10.1128/JVI.00985-20