Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKK
The ongoing COVID-19 pandemic has revealed the shortfalls in our understanding of how to treat coronavirus infections. With almost 7 million case fatalities of COVID-19 globally, the catalog of FDA-approved antiviral therapeutics is limited compared to other medications, such as antibiotics. All-tra...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-01-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/16/1/140 |
| _version_ | 1797342388870447104 |
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| author | Justin H. Franco Ryan A. Harris William G. Ryan Roger Travis Taylor Robert E. McCullumsmith Saurabh Chattopadhyay Zhixing K. Pan |
| author_facet | Justin H. Franco Ryan A. Harris William G. Ryan Roger Travis Taylor Robert E. McCullumsmith Saurabh Chattopadhyay Zhixing K. Pan |
| author_sort | Justin H. Franco |
| collection | DOAJ |
| description | The ongoing COVID-19 pandemic has revealed the shortfalls in our understanding of how to treat coronavirus infections. With almost 7 million case fatalities of COVID-19 globally, the catalog of FDA-approved antiviral therapeutics is limited compared to other medications, such as antibiotics. All-trans retinoic acid (RA), or activated vitamin A, has been studied as a potential therapeutic against coronavirus infection because of its antiviral properties. Due to its impact on different signaling pathways, RA’s mechanism of action during coronavirus infection has not been thoroughly described. To determine RA’s mechanism of action, we examined its effect against a mouse coronavirus, mouse hepatitis virus strain A59 (MHV). We demonstrated that RA significantly decreased viral titers in infected mouse L929 fibroblasts and RAW 264.7 macrophages. The reduced viral titers were associated with a corresponding decrease in MHV nucleocapsid protein expression. Using interferon regulatory factor 3 (IRF3) knockout RAW 264.7 cells, we demonstrated that RA-induced suppression of MHV required IRF3 activity. RNA-seq analysis of wildtype and IRF3 knockout RAW cells showed that RA upregulated calcium/calmodulin (CaM) signaling proteins, such as CaM kinase kinase 1 (CaMKK1). When treated with a CaMKK inhibitor, RA was unable to upregulate IRF activation during MHV infection. In conclusion, our results demonstrate that RA-induced protection against coronavirus infection depends on IRF3 and CaMKK. |
| first_indexed | 2024-03-08T10:32:35Z |
| format | Article |
| id | doaj.art-89be7e9094b6477595294fa78a97a567 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-08T10:32:35Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-89be7e9094b6477595294fa78a97a5672024-01-26T18:48:33ZengMDPI AGViruses1999-49152024-01-0116114010.3390/v16010140Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKKJustin H. Franco0Ryan A. Harris1William G. Ryan2Roger Travis Taylor3Robert E. McCullumsmith4Saurabh Chattopadhyay5Zhixing K. Pan6Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USADepartment of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USADepartment of Neurosciences and Neurological Disorders, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USADepartment of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USADepartment of Neurosciences and Neurological Disorders, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USADepartment of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USADepartment of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USAThe ongoing COVID-19 pandemic has revealed the shortfalls in our understanding of how to treat coronavirus infections. With almost 7 million case fatalities of COVID-19 globally, the catalog of FDA-approved antiviral therapeutics is limited compared to other medications, such as antibiotics. All-trans retinoic acid (RA), or activated vitamin A, has been studied as a potential therapeutic against coronavirus infection because of its antiviral properties. Due to its impact on different signaling pathways, RA’s mechanism of action during coronavirus infection has not been thoroughly described. To determine RA’s mechanism of action, we examined its effect against a mouse coronavirus, mouse hepatitis virus strain A59 (MHV). We demonstrated that RA significantly decreased viral titers in infected mouse L929 fibroblasts and RAW 264.7 macrophages. The reduced viral titers were associated with a corresponding decrease in MHV nucleocapsid protein expression. Using interferon regulatory factor 3 (IRF3) knockout RAW 264.7 cells, we demonstrated that RA-induced suppression of MHV required IRF3 activity. RNA-seq analysis of wildtype and IRF3 knockout RAW cells showed that RA upregulated calcium/calmodulin (CaM) signaling proteins, such as CaM kinase kinase 1 (CaMKK1). When treated with a CaMKK inhibitor, RA was unable to upregulate IRF activation during MHV infection. In conclusion, our results demonstrate that RA-induced protection against coronavirus infection depends on IRF3 and CaMKK.https://www.mdpi.com/1999-4915/16/1/140retinoic acidcoronavirusMHVIRF3CaMKK |
| spellingShingle | Justin H. Franco Ryan A. Harris William G. Ryan Roger Travis Taylor Robert E. McCullumsmith Saurabh Chattopadhyay Zhixing K. Pan Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKK Viruses retinoic acid coronavirus MHV IRF3 CaMKK |
| title | Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKK |
| title_full | Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKK |
| title_fullStr | Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKK |
| title_full_unstemmed | Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKK |
| title_short | Retinoic Acid-Mediated Inhibition of Mouse Coronavirus Replication Is Dependent on IRF3 and CaMKK |
| title_sort | retinoic acid mediated inhibition of mouse coronavirus replication is dependent on irf3 and camkk |
| topic | retinoic acid coronavirus MHV IRF3 CaMKK |
| url | https://www.mdpi.com/1999-4915/16/1/140 |
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