Role of hydrogen sulfide in paramyxovirus infections.
Hydrogen sulfide (H2S) is an endogenous gaseous mediator that has gained increasing recognition as an important player in modulating acute and chronic inflammatory diseases. However, its role in virus-induced lung inflammation is currently unknown. Respiratory syncytial virus (RSV) is a major cause of upper and lower respiratory tract infections in children for which no vaccine or effective treatment is available. Using the slow-releasing H2S donor GYY4137 and propargylglycin (PAG), an inhibitor of cystathionine-γ-lyase (CSE), a key enzyme that produces intracellular H2S, we found that RSV infection led to a reduced ability to generate and maintain intracellular H2S levels in airway epithelial cells (AECs). Inhibition of CSE with PAG resulted in increased viral replication and chemokine secretion. On the other hand, treatment of AECs with the H2S donor GYY4137 reduced proinflammatory mediator production and significantly reduced viral replication, even when administered several hours after viral absorption. GYY4137 also significantly reduced replication and inflammatory chemokine production induced by human metapneumovirus (hMPV) and Nipah virus (NiV), suggesting a broad inhibitory effect of H2S on paramyxovirus infections. GYY4137 treatment had no effect on RSV genome replication or viral mRNA and protein synthesis, but it inhibited syncytium formation and virus assembly/release. GYY4137 inhibition of proinflammatory gene expression occurred by modulation of the activation of the key transcription factors nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF-3) at a step subsequent to their nuclear translocation. H2S antiviral and immunoregulatory properties could represent a novel treatment strategy for paramyxovirus infections.


OBJECTIVE
RSV is a global health concern, causing significant morbidity and economic losses as well as mortality in developing countries. After decades of intensive research, no vaccine or effective treatment, with the exception of immunoprophylaxis, is available for this infection as well as for other important respiratory mucosal viruses. This study identifies hydrogen sulfide as a novel cellular mediator that can modulate viral replication and proinflammatory gene expression, both important determinants of lung injury in respiratory viral infections, with potential for rapid translation of such findings into novel therapeutic approaches for viral bronchiolitis and pneumonia.
Department of Pediatrics, University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
Hui
H
Li
Department of Pediatrics, University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
Yinghong
Y
Ma
Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
Oliver
O
Escaffre
Department of Pediatrics, University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
Teodora
T
Ivanciuc
Department of Pediatrics, University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
Narayana
N
Komaravelli
Department of Pediatrics, University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
John P
JP
Kelley
Department of Anesthesiology, University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
Ciro
C
Coletta
Department of Anesthesiology, University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
Csaba
C
Szabo
Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas, USA Department of Rare and Emerging Viral Infections and Response, Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
Barry
B
Rockx
Department of Pediatrics, University of Texas Medical Branch at Galveston, Galveston, Texas, USA Sealy Center for Vaccine Development, University of Texas Medical Branch at Galveston, Galveston, Texas, USA Sealy Center for Molecular Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas, USA.
Roberto P
RP
Garofalo
Department of Pediatrics, University of Texas Medical Branch at Galveston, Galveston, Texas, USA Sealy Center for Vaccine Development, University of Texas Medical Branch at Galveston, Galveston, Texas, USA Sealy Center for Molecular Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas, USA ancasola@utmb.edu.
Antonella
A
Casola
D000480:Alkynes / Q000494:pharmacology; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D018184:Paramyxoviridae Infections / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D000480:Alkynes; D018925:Chemokines; D004791:Enzyme Inhibitors; C529376:GYY 4137; C494232:IRF3 protein, human; D018836:Inflammation Mediators; D050838:Interferon Regulatory Factor-3; D009025:Morpholines; D016328:NF-kappa B; D009946:Organothiophosphorus Compounds; C009055:propargylglycine; D003542:Cystathionine gamma-Lyase; D005998:Glycine; D006862:Hydrogen Sulfide