Redox control in the pathophysiology of influenza virus infection

Abstract

Triggered in response to external and internal ligands in cells and animals, redox homeostasis is transmitted via signal molecules involved in defense redox mechanisms through networks of cell proliferation, differentiation, intracellular detoxification, bacterial infection, and immune reactions. Cellular oxidation is not necessarily harmful per se, but its effects depend on the balance between the peroxidation and antioxidation cascades, which can vary according to the stimulus and serve to maintain oxygen homeostasis. The reactive oxygen species (ROS) that are generated during influenza virus (IV) infection have critical effects on both the virus and host cells. In this review, we outline the link between viral infection and redox control using IV infection as an example. We discuss the current state of knowledge on the molecular relationship between cellular oxidation mediated by ROS accumulation and the diversity of IV infection. We also summarize the potential anti-IV agents available currently that act by targeting redox biology/pathophysiology.

Keywords: Antioxidation; Aryl hydrocarbon receptor; Cellular oxidation; Nuclear factor E2-related factor 2; Reactive oxygen species.

Fig. 1

Schematic representation of ROS/RNS production and Redox control in response to stresses inducing reagents and influenza virus (IV) infection. Subcellular organelles and cellular components were affected by the oxidation and antioxidation responses in the case of stress inducers like phase I reagents and environmental hormones (Panel a) and infection of IVs (Panel b). The source of cellular ROS/RNS production mainly occurred in mitochondria, endoplasmic reticulum, lipid bilayer, organelle membranes, cellular lipids, DNA in the nuclei, and cellular oxidation enzymes and antioxidation enzymes such as superoxide dismutases (SODs), catalases (CATs), peroxidases (Prdxs), glutathione peroxidase (GPx) and glutaredoxins (GRs) and so on. In addition, the cellular signaling pathways such as NF-kB, MAPK, PI3K, AKT and iNOS signaling are also shown. After IVs infection, NOX produced superoxide (O₂^-) and dysfunction on the mitochondrial proteins. The defective mitochondrial proteins resulted in the leakage of electrons and superoxides from the mitochondria, as well as initiating cell death pathways by cytochrome c or permeability transition pore (PTP). The NF-kB produced many cytokines as well as inducible nitric oxide (NO) synthase (iNOS). This iNOS then produced nitric oxides (NO). The NO and O₂^- reacted together to produce peroxynitrite (ONOO) which is a highly reactive compound to generate the protein nitration and damage of macromolecules. and viral mutations. Higher generation of O₂^- resulted in the production of H₂O₂ by the catalytic activity of SOD. Uncontrolled production of H₂O₂ produced hydroxyl radicals (OH^-) via reaction with metal cations, and these H2O2 and OH^- caused irreversible damages to cellular proteins, lipids, nucleic acids and so on. This Figure is a modified version of the ones published by Di Meo et al. [16] and Kohmich et al. [46].

Fig. 2

Model of infection by influenza viruses of normal host cells and cells overexpressing Nrf2. Infection by IVs led to the production of reactive oxygen species (ROS). Redox control against ROS and viral replication are illustrated. The addition of sulforaphane (SFN) or epigallocatechin gallate (EGCG) inhibits the viral infection of IV via activation of the antioxidation pathway [54].

Fig. 3

Schematic model of the mechanism of ROS production and antioxidation during infection with IVs. During the life cycle of the IV, infection causes oxidative stress reactions in host cells, which leads to induction of Nox1/Nox4 and AhR and the production of ROS, followed by replication of the viruses. Nrf2 and other signaling molecules, such as p38, AKT, and PI3K, are also involved in ROS stress and redox control. Oxidative stress also induces the translocation of the AhR transcription factor to the ER and mitochondria (MIT), which increases ROS production. The antioxidation against ROS by the Nrf2 transcription factor helps to prevent cell damage during the initial phase; however, the excess of ROS causes apoptosis and other types of cellular death in infected host cells. The life cycle of IVs is summarized and the possible targets of drugs to treat IV infection are also indicated.