tetano
Editor, Senior Moderator
J Virol
. 2020 Jul 22;JVI.00985-20.
doi: 10.1128/JVI.00985-20. Online ahead of print.
Type I and Type III IFN Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures
Abigail Vanderheiden[SUP] 1 2 3 [/SUP], Philipp Ralfs[SUP] 2 3 4 [/SUP], Tatiana Chirkova[SUP] 1 2 [/SUP], Amit A Upadhyay[SUP] 2 3 5 [/SUP], Matthew G Zimmerman[SUP] 1 2 3 [/SUP], Shamika Bedoya[SUP] 4 6 [/SUP], Hadj Aoued[SUP] 2 3 5 [/SUP], Gregory M Tharp[SUP] 2 3 5 [/SUP], Kathryn L Pellegrini[SUP] 2 3 5 [/SUP], Candela Manfredi[SUP] 7 [/SUP], Eric Sorscher[SUP] 7 [/SUP], Bernardo Mainou[SUP] 1 [/SUP], Jenna L Lobby[SUP] 4 [/SUP], Jacob E Kohlmeier[SUP] 4 6 [/SUP], Anice C Lowen[SUP] 4 6 [/SUP], Pei-Yong Shi[SUP] 8 [/SUP], Vineet D Menachery[SUP] 9 [/SUP], Larry J Anderson[SUP] 1 2 [/SUP], Arash Grakoui[SUP] 1 2 4 [/SUP], Steven E Bosinger[SUP] 2 3 5 [/SUP], Mehul S Suthar[SUP] 10 2 3 6 [/SUP]
Affiliations
Abstract
The newly emerged human coronavirus, 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. 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, and identified NF-κB and ATF-4 as key drivers of this pro-inflammatory cytokine response. Surprisingly, we observed a complete lack of a type I or III interferon (IFN) response to SARS-CoV-2 infection. However, pre-treatment and post-treatment 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 cultures induce a strong pro-inflammatory 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.
. 2020 Jul 22;JVI.00985-20.
doi: 10.1128/JVI.00985-20. Online ahead of print.
Type I and Type III IFN Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures
Abigail Vanderheiden[SUP] 1 2 3 [/SUP], Philipp Ralfs[SUP] 2 3 4 [/SUP], Tatiana Chirkova[SUP] 1 2 [/SUP], Amit A Upadhyay[SUP] 2 3 5 [/SUP], Matthew G Zimmerman[SUP] 1 2 3 [/SUP], Shamika Bedoya[SUP] 4 6 [/SUP], Hadj Aoued[SUP] 2 3 5 [/SUP], Gregory M Tharp[SUP] 2 3 5 [/SUP], Kathryn L Pellegrini[SUP] 2 3 5 [/SUP], Candela Manfredi[SUP] 7 [/SUP], Eric Sorscher[SUP] 7 [/SUP], Bernardo Mainou[SUP] 1 [/SUP], Jenna L Lobby[SUP] 4 [/SUP], Jacob E Kohlmeier[SUP] 4 6 [/SUP], Anice C Lowen[SUP] 4 6 [/SUP], Pei-Yong Shi[SUP] 8 [/SUP], Vineet D Menachery[SUP] 9 [/SUP], Larry J Anderson[SUP] 1 2 [/SUP], Arash Grakoui[SUP] 1 2 4 [/SUP], Steven E Bosinger[SUP] 2 3 5 [/SUP], Mehul S Suthar[SUP] 10 2 3 6 [/SUP]
Affiliations
- PMID: 32699094
- DOI: 10.1128/JVI.00985-20
Abstract
The newly emerged human coronavirus, 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. 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, and identified NF-κB and ATF-4 as key drivers of this pro-inflammatory cytokine response. Surprisingly, we observed a complete lack of a type I or III interferon (IFN) response to SARS-CoV-2 infection. However, pre-treatment and post-treatment 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 cultures induce a strong pro-inflammatory 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.