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Type I and Type III Interferons Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures.
J Virol. 2020 09 15; 94(19)JV

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.

Authors+Show Affiliations

Center for Childhood Infections and Vaccines (CCIV), Atlanta, Georgia, USA. Children's Healthcare of Atlanta, Atlanta, Georgia, USA. Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA. Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA. Yerkes National Primate Research Center, Atlanta, Georgia, USA.Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA. Yerkes National Primate Research Center, Atlanta, Georgia, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.Center for Childhood Infections and Vaccines (CCIV), Atlanta, Georgia, USA. Children's Healthcare of Atlanta, Atlanta, Georgia, USA. Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA. Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA.Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA. Yerkes National Primate Research Center, Atlanta, Georgia, USA. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.Center for Childhood Infections and Vaccines (CCIV), Atlanta, Georgia, USA. Children's Healthcare of Atlanta, Atlanta, Georgia, USA. Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA. Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA. Yerkes National Primate Research Center, Atlanta, Georgia, USA.Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Emory-UGA Center of Excellence of Influenza Research and Surveillance (CEIRS), Atlanta Georgia, USA.Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA. Yerkes National Primate Research Center, Atlanta, Georgia, USA. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA. Yerkes National Primate Research Center, Atlanta, Georgia, USA. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA. Yerkes National Primate Research Center, Atlanta, Georgia, USA. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.Department of Pediatrics, Division of Pulmonary Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.Department of Pediatrics, Division of Pulmonary Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.Center for Childhood Infections and Vaccines (CCIV), Atlanta, Georgia, USA. Children's Healthcare of Atlanta, Atlanta, Georgia, USA. Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA.Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Emory-UGA Center of Excellence of Influenza Research and Surveillance (CEIRS), Atlanta Georgia, USA.Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. Emory-UGA Center of Excellence of Influenza Research and Surveillance (CEIRS), Atlanta Georgia, USA.Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas, USA.Department of Microbiology and Immunology, Institute for Human Infection and Immunity, World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, Texas, USA.Center for Childhood Infections and Vaccines (CCIV), Atlanta, Georgia, USA. Children's Healthcare of Atlanta, Atlanta, Georgia, USA. Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA. Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA.Center for Childhood Infections and Vaccines (CCIV), Atlanta, Georgia, USA. Children's Healthcare of Atlanta, Atlanta, Georgia, USA. Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA. Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA. Yerkes National Primate Research Center, Atlanta, Georgia, USA. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.Center for Childhood Infections and Vaccines (CCIV), Atlanta, Georgia, USA mehul.s.suthar@emory.edu. Children's Healthcare of Atlanta, Atlanta, Georgia, USA. Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA. Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA. Yerkes National Primate Research Center, Atlanta, Georgia, USA. Emory-UGA Center of Excellence of Influenza Research and Surveillance (CEIRS), Atlanta Georgia, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

32699094

Citation

Vanderheiden, Abigail, et al. "Type I and Type III Interferons Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures." Journal of Virology, vol. 94, no. 19, 2020.
Vanderheiden A, Ralfs P, Chirkova T, et al. Type I and Type III Interferons Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures. J Virol. 2020;94(19).
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). https://doi.org/10.1128/JVI.00985-20
Vanderheiden A, et al. Type I and Type III Interferons Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures. J Virol. 2020 09 15;94(19) PubMed PMID: 32699094.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Type I and Type III Interferons Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures. AU - Vanderheiden,Abigail, AU - Ralfs,Philipp, AU - Chirkova,Tatiana, AU - Upadhyay,Amit A, AU - Zimmerman,Matthew G, AU - Bedoya,Shamika, AU - Aoued,Hadj, AU - Tharp,Gregory M, AU - Pellegrini,Kathryn L, AU - Manfredi,Candela, AU - Sorscher,Eric, AU - Mainou,Bernardo, AU - Lobby,Jenna L, AU - Kohlmeier,Jacob E, AU - Lowen,Anice C, AU - Shi,Pei-Yong, AU - Menachery,Vineet D, AU - Anderson,Larry J, AU - Grakoui,Arash, AU - Bosinger,Steven E, AU - Suthar,Mehul S, Y1 - 2020/09/15/ PY - 2020/05/19/received PY - 2020/07/17/accepted PY - 2020/7/24/pubmed PY - 2020/9/30/medline PY - 2020/7/24/entrez KW - COVID-19 KW - SARS-CoV-2 KW - cytokines KW - innate immunity KW - lung KW - type I interferon JF - Journal of virology JO - J Virol VL - 94 IS - 19 N2 - 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. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/32699094/Type_I_and_Type_III_Interferons_Restrict_SARS_CoV_2_Infection_of_Human_Airway_Epithelial_Cultures_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32699094/ DB - PRIME DP - Unbound Medicine ER -