From vitamin C to G6PD in viral infections (influenza virus, enterovirus, coronavirus, and dengue virus)
Upon viral infection, the innate immune system acts immediately to prevent invading microbes from spreading and moving in the host. The immune responses are closely associated with the redox balance. The redox milieu can modulate viral replication, including HIV, influenza, and respiratory syncytial viruses [44–46]. Antioxidant therapy may prove effective in the prevention of viral infection through redox control [47–50], while insufficient antioxidant capacity is conducive to viral production and virulence [51,52]. For instance, glutathione can inactivate dengue and chikungunya viruses in the blood [53,54]. N-acetylcysteine (NAC) attenuates influenza-like symptoms and COVID-19-induced inflammation [55,56]. On the other hand, selenium deficiency in mice is associated with enhanced enteroviruses virulence and the development of myocardial lesions [57,58]. Glutathione deficiency is linked to HIV progression and poor survival of HIV-infected individuals [59].
Vitamin C, a natural antioxidant and potent free radical scavenger, has long been known for its antiviral effect [60]. The capacity for donating electrons enables vitamin C to support essential cellular processes and immune responses [61–64]. Vitamin C maintains barrier integrity and facilitates wound healing of the skin against oxidative stress and microbial infections [65,66]. Vitamin C is required for chemotaxis, phagocytosis, and microbial clearance in neutrophils [67,68]. It is also necessary for apoptosis and clearance of used neutrophils as well as neutrophil extracellular trap (NET) formation [69,70]. The acidic condition caused by vitamin C helps to convert inorganic nitrate into NO [71]. Lack of vitamin C leads to immune dysfunction and vulnerability to infection. Humans cannot produce vitamin C owing to nonfunctional L-gluconolactone oxidase. Supplementation with a high dose of vitamin C can reduce the symptoms and duration of the common cold [72]. Vitamin C therapy is recognized as a beneficial adjunctive strategy to ameliorate the symptoms of respiratory diseases, including severe acute respiratory disease (SARS) [73]. Glucose competes with the uptake of the oxidized form of vitamin C, dehydroascorbic acid, via the glucose transporter [74]. Hence, the bioavailability of vitamin C can be restricted by hyperglycemia. If diabetic COVID-19 patients have low levels of vitamin C and are not treated with intravenous vitamin C, it may partly explain the severity of their illness. Several clinical trials have been proposed to infuse high dose vitamin C as an intervention for COVID-19 patients [75].
A variety of viruses including calicivirus, hepatitis C virus (HCV), norovirus, rabies, and rubella viruses are sensitive to oxidative stress caused by hydrogen peroxide (H2O2) [76]. H2O2 (0.5%) can inactivate coronavirus within a few minutes [77]. H2O2-containing sanitization products, such as nose or mouth wash, can boost innate immunity and protect against novel coronaviruses in the respiratory tract.
Nitric oxide (NO) is a gaseous free radical that regulates the immune response and provides vascular protection. Vasodilation caused by NO potentially alleviates lung injuries due to COVID-19 [78]. Reduced or disturbed NO metabolism is linked to the disease severity of COVID-19. NO inhalation or a nitrate-rich diet can be beneficial in reversing the pulmonary hypertension and mortality caused by COVID-19 [79,80].
NO production is positively correlated with G6PD activity. G6PD deficiency in human granulocytes abolishes NO production induced by LPS and 12-myristate 13-acetate (PMA) [42]. IL-1β increases NOS expression and NO levels as well as G6PD activity in pancreatic islet cells [81]. Inhibition of G6PD by DHEA or siRNA decreases IL-1β-stimulated NO production. The bioavailability of NO and G6PD status are inversely correlated with ROS in endothelial cells [82]. Less endothelial NOS (eNOS) expression and low levels of NO and GSH are found in G6PD-deficient endothelial cells, while L-cysteine, a GSH precursor, reduces oxidative stress [83]. Peroxynitrite derived from NO is toxic to neurons. It stimulates G6PD activity and causes apoptosis in PC12 cells. NO-mediated apoptotic neuronal cell death can be rescued by G6PD overexpression, while G6PD suppression worsens the apoptosis [84].
G6PD may play an important role in viral infection [9–11,85]. Lack of G6PD promotes cytopathic effects and viral replication. G6PD-deficient cells are susceptible to viral infection, such as coronavirus, dengue virus, and enterovirus [9,85,86]. During human coronavirus 229E or enterovirus 71 infections in G6PD-deficient human lung fibroblasts and epithelial cells, HSCARG, a NADPH sensor, and a negative NF-κB regulator is up-regulated. Knockdown of HSCARG activates NF-κB and induces downstream antiviral gene expression, including TNF-α and MX1 [10]. Downregulation of HSCARG decreases viral gene expression, while the upregulation of HSCARG increases viral replication. This indicates that G6PD activity determines the anti-viral response mediated by HSCARG and the NF-κB pathway.
G6PD deficiency is associated with reduced expression of prostaglandin E2 (PGE2) and its upstream cyclooxygenase-2 (COX-2), which regulates inflammatory and antiviral responses [11]. TNF-α stimulated COX-2 inhibition in G6PD-deficient lung epithelial cells increases the susceptibility to coronavirus infection by the decreased phosphorylation of MAPK and NF-κB levels. The expression of MAPK activation and COX-2 triggered by TNF-α in G6PD-deficient cells can be attenuated by siRNA against NOX or the NOX inhibitor diphenyleneiodonium (DPI), suggesting the involvement of NOX signaling by G6PD [17]. These findings indicate that G6PD is necessary for NOX activation upon TNF-α stimulation in regulating the anti-viral response.