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Type I and Type III IFN 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, View ORCID ProfileAnice C. Lowen, View ORCID ProfileVineet D. Menachery, Larry J. Anderson, Arash Grakoui, Steven E. Bosinger, View ORCID ProfileMehul S. Suthar
doi: https://doi.org/10.1101/2020.05.19.105437
Abigail Vanderheiden
aCenter for Childhood Infections and Vaccines (CCIV); Children’s Healthcare of Atlanta; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322 USA
bEmory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
cYerkes National Primate Research Center, Atlanta, GA 30329, USA
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Philipp Ralfs
bEmory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
cYerkes National Primate Research Center, Atlanta, GA 30329, USA
dDepartment of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA
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Tatiana Chirkova
aCenter for Childhood Infections and Vaccines (CCIV); Children’s Healthcare of Atlanta; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322 USA
bEmory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
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Amit A. Upadhyay
bEmory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
cYerkes National Primate Research Center, Atlanta, GA 30329, USA
eDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
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Matthew G. Zimmerman
aCenter for Childhood Infections and Vaccines (CCIV); Children’s Healthcare of Atlanta; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322 USA
bEmory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
cYerkes National Primate Research Center, Atlanta, GA 30329, USA
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Shamika Bedoya
dDepartment of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA
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Hadj Aoued
bEmory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
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Gregory M. Tharp
bEmory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
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Kathryn L. Pellegrini
bEmory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
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Anice C. Lowen
dDepartment of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA
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  • ORCID record for Anice C. Lowen
Vineet D. Menachery
fDepartment of Microbiology and Immunology, Institute for Human Infection and Immunity, World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA
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Larry J. Anderson
aCenter for Childhood Infections and Vaccines (CCIV); Children’s Healthcare of Atlanta; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322 USA
bEmory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
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Arash Grakoui
aCenter for Childhood Infections and Vaccines (CCIV); Children’s Healthcare of Atlanta; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322 USA
bEmory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
dDepartment of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA
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Steven E. Bosinger
bEmory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
cYerkes National Primate Research Center, Atlanta, GA 30329, USA
eDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
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Mehul S. Suthar
aCenter for Childhood Infections and Vaccines (CCIV); Children’s Healthcare of Atlanta; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322 USA
bEmory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
cYerkes National Primate Research Center, Atlanta, GA 30329, USA
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  • ORCID record for Mehul S. Suthar
  • For correspondence: mehul.s.suthar@emory.edu
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ABSTRACT

The newly emerged human coronavirus, SARS-CoV-2, has caused a pandemic of respiratory illness. The innate immune response is critical for protection against Coronaviruses. However, little is known about the interplay between the innate immune system and SARS-CoV-2. Here, 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 pro-inflammatory cytokines and chemokine induction, including IL-6, TNFα, CXCL8. We also identified NF-κB and ATF4 transcription factors as key drivers of this pro-inflammatory cytokine response. Surprisingly, we observed a complete lack of a type I or III IFN induction during SARS-CoV-2 infection. Pre-treatment or post-treatment with type I and III IFNs dramatically reduced virus replication in pHAE cultures and this corresponded with an upregulation of antiviral effector genes. Our findings demonstrate that SARS-CoV-2 induces a strong pro-inflammatory cytokine response yet blocks the production of type I and III IFNs. Further, SARS-CoV-2 is sensitive to the effects of type I and III IFNs, demonstrating their potential utility 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 or antivirals approved for use in humans, studies of the mechanisms of SARS-CoV-2 infection are urgently needed. SARS-CoV-2 infection of primary human airway epithelial cultures induces a strong pro-inflammatory cytokine response yet blocks the production of type I and III IFNs. Further, SARS-CoV-2 is sensitive to the effects of type I and III IFNs, demonstrating their potential utility as therapeutic options to treat COVID-19 patients.

Footnotes

  • Lead contact: Mehul S. Suthar (mehul.s.suthar{at}emory.edu)

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Posted May 20, 2020.
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Type I and Type III IFN 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, Anice C. Lowen, Vineet D. Menachery, Larry J. Anderson, Arash Grakoui, Steven E. Bosinger, Mehul S. Suthar
bioRxiv 2020.05.19.105437; doi: https://doi.org/10.1101/2020.05.19.105437
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Type I and Type III IFN 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, Anice C. Lowen, Vineet D. Menachery, Larry J. Anderson, Arash Grakoui, Steven E. Bosinger, Mehul S. Suthar
bioRxiv 2020.05.19.105437; doi: https://doi.org/10.1101/2020.05.19.105437

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