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bioRxiv · 10.1101/2024.12.29.630646

Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection.

Agrawal, R.·Pal, V. K.·S, S. K.·Menon, G. J.·Singh, I. R.·Malhotra, N.·S, N. C.·Ganesh, K.·Rajmani, R. S.·Seshasayee, A. S. N.·Chandra, N.·Joshi, M. B.·Singh, A.
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Abstract

Viruses exploit host metabolism for replication and immune-regulation. 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-{beta}-synthase (CBS), cystathionine-{gamma}-lyase (CTH), and 3-mercaptopyruvate sulfurtransferase (3-MST), resulting in diminished endogenous H2S levels. Inhibition of CTH resulted in SARS-CoV-2 proliferation. A slow-releasing H2S donor, GYY4137, diminished virus replication by inducing Nrf2/Keap1 pathway, restoring redox balance and mitochondrial bioenergetics. Treatment of SARS-CoV-2-infected animals with GYY4137 suppressed viral replication, ameliorated respiratory pathology, and restored antioxidant gene expression. Notably, whole-body plethysmography showed improved pulmonary function variables, including pulmonary obstruction and end-expiratory pause upon GYY4137 treatment in vivo. Data 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.

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Agrawal, R., Pal, V. K., S, S. K., Menon, G. J., Singh, I. R., Malhotra, N., S, N. C., Ganesh, K., Rajmani, R. S., Seshasayee, A. S. N., Chandra, N., Joshi, M. B., Singh, A.. 2024-12-30. Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection.. https://doi.org/10.1101/2024.12.29.630646

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