NADPH Oxidases as Novel Pharmacologic Targets against Influenza A Virus Infection

Abstract

Influenza A viruses represent a major global health care challenge, with imminent pandemics, emerging antiviral resistance, and long lag times for vaccine development, raising a pressing need for novel pharmacologic strategies that ideally target the pathology irrespective of the infecting strain. Reactive oxygen species (ROS) pervade all facets of cell biology with both detrimental and protective properties. Indeed, there is compelling evidence that activation of the NADPH oxidase 2 (NOX2) isoform of the NADPH oxidase family of ROS-producing enzymes promotes lung oxidative stress, inflammation, injury, and dysfunction resulting from influenza A viruses of low to high pathogenicity, as well as impeding virus clearance. By contrast, the dual oxidase isoforms produce ROS that provide vital protective antiviral effects for the host. In this review, we propose that inhibitors of NOX2 are better alternatives than broad-spectrum antioxidant approaches for treatment of influenza pathologies, for which clinical efficacy may have been limited owing to poor bioavailability and inadvertent removal of beneficial ROS. Finally, we briefly describe the current suite of NADPH oxidase inhibitors and the molecular features of the NADPH oxidase enzymes that could be exploited by drug discovery for development of more specific and novel inhibitors to prevent or treat disease caused by influenza.

Novel endosomal NOX2 oxidase inhibitor ameliorates pandemic influenza A virus‐induced lung inflammation in mice

“…Therefore, targeting the primary source of ROS production in inflammatory cells, that is the NOX2‐containing NADPH oxidase to attenuate ROS generation, may be an effective means for reducing the ROS‐induced viral burden and tissue damage. To support this notion, the specific deletion of the NOX2 gene was associated with improved lung function and a reduced amount of lung tissue damage . Our recent findings revealed that the primary subcellular site of ROS generation to influenza virus infection is the endosome .…”

Endosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy

“…ROS, such as superoxide anion and hydrogen peroxide (H 2 O 2 ), are produced by mouse and human inflammatory cells in response to viral infection and enhance the pathology caused by viruses of low to high pathogenicity, including influenza A viruses 3–8 . The primary source of inflammatory cell ROS is the NOX2 oxidase enzyme 8–11 .…”

“…The primary source of inflammatory cell ROS is the NOX2 oxidase enzyme 8–11 . Although NOX2 oxidase plays a role in the killing of bacteria and fungi via phagosomal ROS production, NOX2 oxidase does not appear to eliminate viruses in a manner analogous to that for bacteria.…”

“…Although NOX2 oxidase plays a role in the killing of bacteria and fungi via phagosomal ROS production, NOX2 oxidase does not appear to eliminate viruses in a manner analogous to that for bacteria. In fact, in the absence of NOX2, influenza A virus causes substantially less lung injury and dysfunction, and leads to lower viral burden suggesting that NOX2 oxidase-derived ROS promotes rather than inhibits viral infection 3–8 . However, it remains unknown how viruses cause ROS production and how these highly reactive oxygen molecules, which appear to be largely confined to their site of generation, contribute to disease.…”

High-throughput screening of cellular redox sensors using modern redox proteomics approaches

“…Specifically, low levels of ROS contribute to tumorigenesis either by stimulating DNA mutation or acting as second messengers involved in cancer cell survival [9,10], whereas high levels of ROS are linked to damage of cellular components, leading to cancer cell death [9]. In addition, it is experimentally confirmed that ROS are also involved in other diseases, including virus infection, neurodegenerative diseases, cardiovascular diseases, and immune disorder [11][12][13][14]. Unraveling the molecular mechanisms underlying redox regulation in cancer cells is therefore important and will assist in the development of novel therapeutic strategies.…”