Influenza Virus Down-Modulates G6PD Expression and Activity to Induce Oxidative Stress and Promote Its Replication

Abstract

Influenza virus infection induces oxidative stress in host cells by decreasing the intracellular content of glutathione (GSH) and increasing reactive oxygen species (ROS) level. Glucose-6-phosphate dehydrogenase (G6PD) is responsible for the production of reducing equivalents of nicotinamide adenine dinucleotide phosphate (NADPH) that is used to regenerate the reduced form of GSH, thus restoring redox homeostasis. Cells deficient in G6PD display elevated levels of ROS and an increased susceptibility to viral infection, although the consequences of G6PD modulation during viral infection remain to be elucidated. In this study, we demonstrated that influenza virus infection decreases G6PD expression and activity, resulting in an increase in oxidative stress and virus replication. Moreover, the down regulation of G6PD correlated with a decrease in the expression of nuclear factor erythroid 2-related factor 2 (NRF2), a key transcription factor that regulates the expression of the antioxidant response gene network. Also down-regulated in influenza virus infected cells was sirtuin 2 (SIRT2), a NADPH-dependent deacetylase involved in the regulation of G6PD activity. Acetylation of G6PD increased during influenza virus infection in a manner that was strictly dependent on SIRT2 expression. Furthermore, the use of a pharmacological activator of SIRT2 rescued GSH production and NRF2 expression, leading to decreased influenza virus replication. Overall, these data identify a novel strategy used by influenza virus to induce oxidative stress and to favor its replication in host cells. These observations furthermore suggest that manipulation of metabolic and oxidative stress pathways could define new therapeutic strategies to interfere with influenza virus infection.

Lignans from Mosla scabra Ameliorated Influenza A Virus-Induced Pneumonia via Inhibiting Macrophage Activation

“…During influenza virus infection, the monocytes/macrophages are recruited from the cycle into the damaged areas of lung tissues to repair the injury and clear the virus, producing and releasing a variety of factors, including proinflammatory cytokines (TNF- α , IL-1 β , and IL-6), antiviral cytokines (IFN- α / γ ) and chemokines (MCP-1), which are directly or indirectly involved in the antiviral response. The immune response induced by these mediators is beneficial to the organism, but if induced excessively, it can be transformed into an immunopathological response, causing destruction of self-cells and inflammatory damage to lung tissues [ 5 , 33 – 35 ].…”

“…Likewise, TNF- α and IL-1 β are the important proinflammatory cytokines involved in the host immune and the initiators of the inflammatory response. Numerous animal experiments and clinical trials demonstrated a strong link between their increased circulating levels and host inflammatory response [ 5 , 36 ]. Viral stimulation can cause activation of PLA 2 , which acts on cell membrane phospholipids to produce arachidonic acid, whose metabolites include leukotrienes (LTs) and prostaglandin products (PGs) [ 37 ].…”

“…In uenza virus infection stimulates alveolar macrophages to produce excessive inammatory factors, in ammatory mediators, and oxygenfree radicals, which intensify the in ammatory response in the lung [2]. Studies show that the lethal consequences of in uenza virus infection in mice depend more on immunopathological damage to the host than on direct cellular damage due to virus replication [3][4][5]. erefore, blocking macrophage activation is important for the control of inuenza virus-induced immune in ammation.…”

Reactive oxygen species associated immunoregulation post influenza virus infection

“…Apart from the three main mechanisms, other mechanisms of IAV to produce ROS and favor its replication have been proposed. In human lung cancer A549 cells, decreased sirtuin 2 (SIRT2) reduces the expression and activity of glucose-6phosphate dehydrogenase (G6PD) by acetylation, resulting in enhanced production of ROS and IAV replication (22). The binding between aryl hydrocarbon receptor (AhR) and its ligand, quinone 1 (NQO1) is also reported to involve in the production of ROS (5,23,24).…”

Ultrastructural Damages to H1N1 Influenza Virus Caused by Vapor Essential Oils

“…The Cytopathic Effect (CPE) induced by the infection was evaluated 24 h post infection and TCID 50 was calculated using the Reed-Muench method, as previously reported [50]. Dried virus, not exposed to any oil, was diluted in PBS and used as control.…”