Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection.
Viruses modulate various aspects of host physiology, including carbon metabolism, redox balance, and mitochondrial bioenergetics to acquire the building blocks for replication and regulation of the immune response. Understanding how SARS-CoV-2 alters the host metabolism may lead to treatments for CO...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-05-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1013164 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849337633883291648 |
|---|---|
| author | Ragini Agrawal Virender Kumar Pal Suhas K S Gopika Jayan Menon Inder Raj Singh Nitish Malhotra Naren C S Kailash Ganesh Raju S Rajmani Aswin Sai Narain Seshasayee Nagasuma Chandra Manjunath B Joshi Amit Singh |
| author_facet | Ragini Agrawal Virender Kumar Pal Suhas K S Gopika Jayan Menon Inder Raj Singh Nitish Malhotra Naren C S Kailash Ganesh Raju S Rajmani Aswin Sai Narain Seshasayee Nagasuma Chandra Manjunath B Joshi Amit Singh |
| author_sort | Ragini Agrawal |
| collection | DOAJ |
| description | Viruses modulate various aspects of host physiology, including carbon metabolism, redox balance, and mitochondrial bioenergetics to acquire the building blocks for replication and regulation of the immune response. Understanding how SARS-CoV-2 alters the host metabolism may lead to treatments for COVID-19. We report that a ubiquitous gaseous molecule, hydrogen sulfide (H2S), regulates redox, metabolism, and mitochondrial bioenergetics to control SARS-CoV-2. Virus replication is associated with down-regulation of the H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CTH), and 3-mercaptopyruvate sulfurtransferase (3-MST) in multiple cell lines and nasopharyngeal swabs of symptomatic COVID-19 patients. Consequently, SARS-CoV-2-infected cells showed diminished endogenous H2S levels and a protein modification (S-sulfhydration) caused by H2S. Genetic silencing or chemical inhibition of CTH resulted in SARS-CoV-2 proliferation. Chemical supplementation of H2S using a slow-releasing H2S donor, GYY4137, diminished virus replication. Using a redox biosensor, metabolomics, transcriptomics, and XF-flux analyzer, we showed that GYY4137 blocked SARS-CoV-2 replication by inducing the Nrf2/Keap1 pathway, restoring redox balance and carbon metabolites and potentiating mitochondrial oxidative phosphorylation. Treatment of SARS-CoV-2-infected mice or hamsters with GYY4137 suppressed viral replication and ameliorated lung pathology. GYY4137 treatment reduced the expression of inflammatory cytokines and re-established the expression of Nrf2-dependent antioxidant genes in the lungs of SARS-CoV-2-infected mice. Notably, non-invasive measurement of respiratory functions using unrestrained whole-body plethysmography (uWBP) of SARS-CoV-2-infected mice showed improved pulmonary function variables, including pulmonary obstruction (Penh), end-expiratory pause (EEP), and relaxation time (RT) upon GYY4137 treatment. Together, our findings significantly extend our understanding of H2S-mediated regulation of viral infections and open new avenues for investigating the pathogenic mechanisms and therapeutic opportunities for coronavirus-associated disorders. |
| format | Article |
| id | doaj-art-b78d8d21c6a04e1d8569804a0a8faa75 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-b78d8d21c6a04e1d8569804a0a8faa752025-08-20T03:44:38ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-05-01215e101316410.1371/journal.ppat.1013164Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection.Ragini AgrawalVirender Kumar PalSuhas K SGopika Jayan MenonInder Raj SinghNitish MalhotraNaren C SKailash GaneshRaju S RajmaniAswin Sai Narain SeshasayeeNagasuma ChandraManjunath B JoshiAmit SinghViruses modulate various aspects of host physiology, including carbon metabolism, redox balance, and mitochondrial bioenergetics to acquire the building blocks for replication and regulation of the immune response. Understanding how SARS-CoV-2 alters the host metabolism may lead to treatments for COVID-19. We report that a ubiquitous gaseous molecule, hydrogen sulfide (H2S), regulates redox, metabolism, and mitochondrial bioenergetics to control SARS-CoV-2. Virus replication is associated with down-regulation of the H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CTH), and 3-mercaptopyruvate sulfurtransferase (3-MST) in multiple cell lines and nasopharyngeal swabs of symptomatic COVID-19 patients. Consequently, SARS-CoV-2-infected cells showed diminished endogenous H2S levels and a protein modification (S-sulfhydration) caused by H2S. Genetic silencing or chemical inhibition of CTH resulted in SARS-CoV-2 proliferation. Chemical supplementation of H2S using a slow-releasing H2S donor, GYY4137, diminished virus replication. Using a redox biosensor, metabolomics, transcriptomics, and XF-flux analyzer, we showed that GYY4137 blocked SARS-CoV-2 replication by inducing the Nrf2/Keap1 pathway, restoring redox balance and carbon metabolites and potentiating mitochondrial oxidative phosphorylation. Treatment of SARS-CoV-2-infected mice or hamsters with GYY4137 suppressed viral replication and ameliorated lung pathology. GYY4137 treatment reduced the expression of inflammatory cytokines and re-established the expression of Nrf2-dependent antioxidant genes in the lungs of SARS-CoV-2-infected mice. Notably, non-invasive measurement of respiratory functions using unrestrained whole-body plethysmography (uWBP) of SARS-CoV-2-infected mice showed improved pulmonary function variables, including pulmonary obstruction (Penh), end-expiratory pause (EEP), and relaxation time (RT) upon GYY4137 treatment. Together, our findings significantly extend our understanding of H2S-mediated regulation of viral infections and open new avenues for investigating the pathogenic mechanisms and therapeutic opportunities for coronavirus-associated disorders.https://doi.org/10.1371/journal.ppat.1013164 |
| spellingShingle | Ragini Agrawal Virender Kumar Pal Suhas K S Gopika Jayan Menon Inder Raj Singh Nitish Malhotra Naren C S Kailash Ganesh Raju S Rajmani Aswin Sai Narain Seshasayee Nagasuma Chandra Manjunath B Joshi Amit Singh Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection. PLoS Pathogens |
| title | Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection. |
| title_full | Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection. |
| title_fullStr | Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection. |
| title_full_unstemmed | Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection. |
| title_short | Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection. |
| title_sort | hydrogen sulfide h2s coordinates redox balance carbon metabolism and mitochondrial bioenergetics to suppress sars cov 2 infection |
| url | https://doi.org/10.1371/journal.ppat.1013164 |
| work_keys_str_mv | AT raginiagrawal hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection AT virenderkumarpal hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection AT suhasks hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection AT gopikajayanmenon hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection AT inderrajsingh hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection AT nitishmalhotra hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection AT narencs hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection AT kailashganesh hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection AT rajusrajmani hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection AT aswinsainarainseshasayee hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection AT nagasumachandra hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection AT manjunathbjoshi hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection AT amitsingh hydrogensulfideh2scoordinatesredoxbalancecarbonmetabolismandmitochondrialbioenergeticstosuppresssarscov2infection |