IFN-γ-mediated control of SARS-CoV-2 infection through nitric oxide
Bruno J De Andrade Silva, Paul A Krogstad, Rosane M B Teles, Priscila R Andrade, Jacob Rajfer, Monica G Ferrini, Otto O Yang, Barry R Bloom, Robert L Modlin
Frontiers in Immunology, doi:10.3389/fimmu.2023.1284148
Introduction: The COVID-19 pandemic has highlighted the need to identify mechanisms of antiviral host defense against SARS-CoV-2. One such mediator is interferon-g (IFN-g), which, when administered to infected patients, is reported to result in viral clearance and resolution of pulmonary symptoms. IFN-g treatment of a human lung epithelial cell line triggered an antiviral activity against SARS-CoV-2, yet the mechanism for this antiviral response was not identified. Methods: Given that IFN-g has been shown to trigger antiviral activity via the generation of nitric oxide (NO), we investigated whether IFN-g induction of antiviral activity against SARS-CoV-2 infection is dependent upon the generation of NO in human pulmonary epithelial cells. We treated the simian epithelial cell line Vero E6 and human pulmonary epithelial cell lines, including A549-ACE2, and Calu-3, with IFN-g and observed the resulting induction of NO and its effects on SARS-CoV-2 replication. Pharmacological inhibition of inducible nitric oxide synthase (iNOS) was employed to assess the dependency on NO production. Additionally, the study examined the effect of interleukin-1b (IL-1b) on the IFN-g-induced NO production and its antiviral efficacy. Results: Treatment of Vero E6 cells with IFN-g resulted in a dose-responsive induction of NO and an inhibitory effect on SARS-CoV-2 replication. This antiviral activity was blocked by pharmacologic inhibition of iNOS. IFN-g also triggered a NO-mediated antiviral activity in SARS-CoV-2 infected human lung epithelial cell lines A549-ACE2 and Calu-3. IL-1b enhanced IFN-g induction of NO, but it had little effect on antiviral activity. Discussion: Given that IFN-g has been shown to be produced by CD8+ T cells in the early response to SARS-CoV-2, our findings in human lung epithelial cell lines,
Ethics statement Ethical approval was not required for the studies on humans in accordance with the local legislation and institutional requirements because only commercially available established cell lines were used.
Author contributions
Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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Supplementary material The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1284148/ full#supplementary-material
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doi:10.1056/NEJMoa2001017{ 'DOI': '10.3389/fimmu.2023.1284148',
'ISSN': ['1664-3224'],
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'abstract': '<jats:sec><jats:title>Introduction</jats:title><jats:p>The COVID-19 pandemic has highlighted '
'the need to identify mechanisms of antiviral host defense against SARS-CoV-2. One such '
'mediator is interferon-g (IFN-γ), which, when administered to infected patients, is reported '
'to result in viral clearance and resolution of pulmonary symptoms. IFN-γ treatment of a human '
'lung epithelial cell line triggered an antiviral activity against SARS-CoV-2, yet the '
'mechanism for this antiviral response was not '
'identified.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Given that '
'IFN-γ has been shown to trigger antiviral activity via the generation of nitric oxide (NO), '
'we investigated whether IFN-γ induction of antiviral activity against SARS-CoV-2 infection is '
'dependent upon the generation of NO in human pulmonary epithelial cells. We treated the '
'simian epithelial cell line Vero E6 and human pulmonary epithelial cell lines, including '
'A549-ACE2, and Calu-3, with IFN-γ and observed the resulting induction of NO and its effects '
'on SARS-CoV-2 replication. Pharmacological inhibition of inducible nitric oxide synthase '
'(iNOS) was employed to assess the dependency on NO production. Additionally, the study '
'examined the effect of interleukin-1b (IL-1β) on the IFN-g-induced NO production and its '
'antiviral '
'efficacy.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Treatment of '
'Vero E6 cells with IFN-γ resulted in a dose-responsive induction of NO and an inhibitory '
'effect on SARS-CoV-2 replication. This antiviral activity was blocked by pharmacologic '
'inhibition of iNOS. IFN-γ also triggered a NO-mediated antiviral activity in SARS-CoV-2 '
'infected human lung epithelial cell lines A549-ACE2 and Calu-3. IL-1β enhanced IFN-γ '
'induction of NO, but it had little effect on antiviral '
'activity.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>Given that '
'IFN-g has been shown to be produced by CD8+ T cells in the early response to SARS-CoV-2, our '
'findings in human lung epithelial cell lines, of an IFN-γ-triggered, NO-dependent, links the '
'adaptive immune response to an innate antiviral pathway in host defense against SARS-CoV-2. '
'These results underscore the importance of IFN-γ and NO in the antiviral response and provide '
'insights into potential therapeutic strategies for COVID-19.</jats:p></jats:sec>',
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