Abstract
Highly pathogenic H5N1 infections are often accompanied by excessive pro-inflammatory response, high viral titer, and apoptosis; as such, the efficient control of these infections poses a great challenge. The pathogenesis of influenza virus infection is also related to oxidative stress. However, the role of endogenic genes with antioxidant effect in the control of influenza viruses, especially H5N1 viruses, should be further investigated. In this study, the H5N1 infection in lung epithelial cells decreased Cu/Zn superoxide dismutase (SOD1) expression at mRNA and protein levels. Forced SOD1 expression significantly inhibited the H5N1-induced increase in reactive oxygen species, decreased pro-inflammatory response, prevented p65 and p38 phosphorylation, and impeded viral ribonucleoprotein nuclear export and viral replication. The SOD1 overexpression also rescued H5N1-induced cellular apoptosis and alleviated H5N1-caused mitochondrial dysfunction. Therefore, this study described the role of SOD1 in the replication of H5N1 influenza virus and emphasized the relevance of this enzyme in the control of H5N1 replication in epithelial cells. Pharmacological modulation or targeting SOD1 may open a new way to fight H5N1 influenza virus.
Highlights
H5N1 avian influenza virus infections have spread worldwide and have caused remarkable economic and social impacts, which have raised serious worldwide concerns on a potential influenza pandemic
This study demonstrates that H5N1 influenza virus infection can enhance reactive oxygen species (ROS) production to a greater extent than H1N1 influenza virus and that the former can induce intensive oxidative stress in A549 cells
Considering that SOD1 acts as an important antioxidant enzyme, we investigated whether its Considering that SOD1 acts as an important antioxidant enzyme, we investigated whether its overexpression can reduce H5N1-induced ROS production
Summary
H5N1 avian influenza virus infections have spread worldwide and have caused remarkable economic and social impacts, which have raised serious worldwide concerns on a potential influenza pandemic. Lung epithelial cells are a source of ROS because influenza virus can induce oxidative stress response in cultured airway epithelial cells [15,16]. Overexpression can prevent influenza-induced lung injury in mice by attenuating oxidative stress [22]. SOD1 overexpression can reduce neurotoxic inflammatory signaling in microglial cells by altering ROS production [24]. This study demonstrates that H5N1 influenza virus infection can enhance ROS production to a greater extent than H1N1 influenza virus and that the former can induce intensive oxidative stress in A549 cells. Forced SOD1 expression significantly decreases H5N1-induced ROS production and viral titer This negative regulation of viral replication can be attributed to apoptosis inhibition, pro-inflammatory response attenuation, and protection against mitochondrial damage induced by H5N1 infection. Strategies targeting SOD1 may be an efficient way to control H5N1 infection
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