Hydrogen Sulfide Donor GYY4137 Rescues NRF2 Activation in Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) can cause severe respiratory illness in infants, immunocompromised, and older adults. Despite its burden, no vaccine or specific treatment is available. RSV infection is associated with increased reactive oxygen species (ROS) production, degradation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), and decreased antioxidant enzymes (AOEs), leading to oxidative damage and lung injury. Hydrogen sulfide (H2S) is an endogenous gaseous molecule that plays a physiological role in numerous cellular processes and a protective role in multiple pathological conditions, displaying vasoactive, cytoprotective, anti-inflammatory, and antioxidant activities. H2S can promote NRF2 activation through the sulfhydration of Kelch-like ECH-associated protein 1, the cytoplasmic repressor of NRF2. Here we investigated whether increasing cellular H2S levels could rescue NRF2 and NRF2-dependent gene expression in RSV-infected primary airway epithelial cells. We found that treatment with the H2S donor GYY4137 significantly increased NRF2 levels and AOEs gene expression by decreasing KEAP1 levels, and by modulating pathways involved in RSV-induced NRF2 degradation, such as NRF2 ubiquitination, and promyelocytic leukemia (PML) protein levels. These results suggest that the administration of exogenous H2S can positively impact the altered redox balance associated with RSV infection, which represents an important determinant of RSV-induced lung disease.

Inflammation Related to Association of Low Uric Acid and Progression to Severe Disease in Patients Hospitalized for Non-Severe Coronavirus Disease 2019

“…On the other hand, the administration of steroids, an anti-inflammatory medication, has been shown to reduce the level of severity [ 7 , 38 , 42 ]. In addition, other reports have noted that the administration of antioxidants resulted in reductions in inflammation and severity in respiratory viral infection cases [ 43 , 44 , 45 ], with similar effects expected in patients affected by COVID-19 [ 5 , 34 ]. Additionally, uric acid has been shown to gain an antioxidant property by scavenging ROS, such as singlet oxygen, and peroxyl and hydroxyl radicals, and is also known to provide approximately half of the free radical-scavenging capacity in the human body [ 8 , 46 ].…”

Oxidative stress and ROS-mediated cellular events in RSV infection: potential protective roles of antioxidants

“…Most of these ROS-mediated cellular events seem to do more harm than good in RSV infection. Substantial evidence has shown the beneficial effects of antioxidant treatment in severe RSV infection, such as inhibition of RSV replication and improvement of barrier dysfunction and lung inflammatory injury [ 15 , 50 , 62 , 163 , 165 ]. In addition, zinc is a stable divalent cation and does not directly undergo redox reactions, but it is involved in regulating the oxidant/antioxidant balance [ 166 ].…”

“…Upregulating the expression of Nrf2 and AOEs can reduce RSV infection in human lung epithelial cells and mitigate RSV-induced injury and oxidative stress in mice [ 53 , 61 ]. A recent study indicated that the H 2 S donor GYY4137 decreases Keap1 levels and modulates pathways involved in RSV-induced Nrf2 degradation, contributeing to the significantly increased Nrf2 levels and AOE gene expression, which could be explored as a potential therapeutic application in RSV infection [ 62 ].…”

Hydrogen Sulfide Improves Angiogenesis by Regulating the Transcription of pri-miR-126 in Diabetic Endothelial Cells

“…In addition, we do not know how H 2 S decreases the DNMT1 mRNA level. mRNA production is regulated by transcription factors and transcription repressors, and H 2 S can regulate the expression of transcription factors [ 50 , 51 ]. Considering H 2 S decreases the DNMT1 protein level via limiting its mRNA, we think H 2 S regulates DNMT1 at the transcriptional level.…”