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Respiratory Viral Infections and Subversion of Cellular Antioxidant Defenses.

Komaravelli N, Casola A - J Pharmacogenomics Pharmacoproteomics (2014)

Bottom Line: They also reduce antioxidant enzyme (AOE) levels and/or activity, leading to unbalanced oxidative-antioxidant status and subsequent oxidative cell damage.While exposure to several pro-oxidant stimuli usually leads to Nrf2 activation and upregulation of AOE expression, respiratory viral infections are associated with inhibition of AOE expression/activity, which in the case of RSV and hMPV is associated with reduced Nrf2 nuclear localization, decreased cellular levels and reduced ARE-dependent gene transcription.Therefore, administration of antioxidant mimetics or Nrf2 inducers represents potential viable therapeutic approaches to viral-induced diseases, such as respiratory infections and other infections associated with decreased cellular antioxidant capacity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA.

ABSTRACT

Reactive oxygen species (ROS) formation is part of normal cellular aerobic metabolism, due to respiration and oxidation of nutrients in order to generate energy. Low levels of ROS are involved in cellular signaling and are well controlled by the cellular antioxidant defense system. Elevated levels of ROS generation due to pollutants, toxins and radiation exposure, as well as infections, are associated with oxidative stress causing cellular damage. Several respiratory viruses, including respiratory syncytial virus (RSV), human metapneumovirus (hMPV) and influenza, induce increased ROS formation, both intracellularly and as a result of increased inflammatory cell recruitment at the site of infection. They also reduce antioxidant enzyme (AOE) levels and/or activity, leading to unbalanced oxidative-antioxidant status and subsequent oxidative cell damage. Expression of several AOE is controlled by the activation of the nuclear transcription factor NF-E2-related factor 2 (Nrf2), through binding to the antioxidant responsive element (ARE) present in the AOE gene promoters. While exposure to several pro-oxidant stimuli usually leads to Nrf2 activation and upregulation of AOE expression, respiratory viral infections are associated with inhibition of AOE expression/activity, which in the case of RSV and hMPV is associated with reduced Nrf2 nuclear localization, decreased cellular levels and reduced ARE-dependent gene transcription. Therefore, administration of antioxidant mimetics or Nrf2 inducers represents potential viable therapeutic approaches to viral-induced diseases, such as respiratory infections and other infections associated with decreased cellular antioxidant capacity.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the proposed mechanisms of oxidative cell damage during RSV infectionRSV infection of airway epithelial cells leads to increased superoxide formation and increased H2O2 production, due to up regulation of SOD 2 expression and activity. RSV-induced inhibition of Nrf2 activation, due to proteasome-dependent degradation, causes a progressive decrease in the expression of a variety of AOEs involved in H2O2 detoxification leading to accumulation of highly reactive radicals, such as hydroxyl radical, and subsequent cellular damage (* autoxidation in presence of transition metals).
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Figure 2: Schematic representation of the proposed mechanisms of oxidative cell damage during RSV infectionRSV infection of airway epithelial cells leads to increased superoxide formation and increased H2O2 production, due to up regulation of SOD 2 expression and activity. RSV-induced inhibition of Nrf2 activation, due to proteasome-dependent degradation, causes a progressive decrease in the expression of a variety of AOEs involved in H2O2 detoxification leading to accumulation of highly reactive radicals, such as hydroxyl radical, and subsequent cellular damage (* autoxidation in presence of transition metals).

Mentions: The exact mechanism of decreased expression of AOEs during RSV infection, as well in the context of other viral respiratory infections, is largely unknown. Most of the AOE gene expression is regulated in part through ARE sequences and Nrf2 activity [30,67]. Transcription factor Nrf2 is an important redox-responsive protein that protects the cells from oxidative stress and injury (Reviewed in [16]). Nrf2-dependent AOE gene expression might be reduced by: (i) competition for binding to the ARE site - Bach1/small Maf protein complex or AP-1 family transcription factors like c-Fos and FRA1 can bind to ARE acting as a transcriptional repressor [67,68]; (ii) preventing Nrf2 activation through direct physical association - Activating transcription factor (ATF)3 or retinoic acid receptor α were shown to form inhibitory complexes with Nrf2, leading to displacement from ARE elements; (iii) interfering with recruitment of co activators, such as CBP, to the ARE site - NF-κB activation can lead to decreased availability of CBP and promote the recruitment of co repressors (histone deacetylases) at Nrf2-ARE site [67]; (iv) reduced nuclear levels, which can occur due to enhanced nuclear to cytoplasm efflux or increased Nrf2 degradation [8]. A recent study has shown that RSV infection in Nrf2−/− mice is more severe and associated with higher viral titers, augmented inflammation, enhanced mucus production and epithelial injury compared to Nrf2 wild type mice, indicating the protective role of Nrf2-ARE pathway against RSV infection [69]. RSV infection can indeed induced a progressive decrease in ARE-dependent gene transcription in A549 cells, carcinoma-derived type II-like airway epithelial cells, investigated using luciferase reporter gene assays (Figure 1A, left panel)[47]. A similar result was obtained when cells were infected with hMPV (Figure 1A, right panel). Reduced nuclear levels of Nrf2 was observed in both RSV infection (Figure 1B, left panel) [8] and hMPV infection (Figure 1B, right panel), together with increased nuclear levels of known ARE transcriptional repressors such as Bach1 and ATF3 (Casola A, unpublished observation) [47], suggesting a potential mechanism for viral-induced down regulation of AOE gene expression. As Nrf2 positively regulates its own gene transcription, reduced Nrf2 mRNA levels were observed in airway epithelial cells at late time point of RSV infection [8]. Our recent studies indicate that RSV infection is associated with Nrf2 deacetylation, likely due to RSV-induced upregulation of histone deacetylase (HDAC) activity, and increased degradation, which occurs through the ubiquitin-proteasome pathway. Blocking proteasome and class I HDAC activity, in particular HDAC 1 and 2, rescued Nrf2 activation and ARE-dependent gene expression during RSV infection (Casola A, unpublished observation). A summary of findings and a proposed model of RSV-induced oxidative stress in airway epithelial cells are depicted in Figure 2.


Respiratory Viral Infections and Subversion of Cellular Antioxidant Defenses.

Komaravelli N, Casola A - J Pharmacogenomics Pharmacoproteomics (2014)

Schematic representation of the proposed mechanisms of oxidative cell damage during RSV infectionRSV infection of airway epithelial cells leads to increased superoxide formation and increased H2O2 production, due to up regulation of SOD 2 expression and activity. RSV-induced inhibition of Nrf2 activation, due to proteasome-dependent degradation, causes a progressive decrease in the expression of a variety of AOEs involved in H2O2 detoxification leading to accumulation of highly reactive radicals, such as hydroxyl radical, and subsequent cellular damage (* autoxidation in presence of transition metals).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4288774&req=5

Figure 2: Schematic representation of the proposed mechanisms of oxidative cell damage during RSV infectionRSV infection of airway epithelial cells leads to increased superoxide formation and increased H2O2 production, due to up regulation of SOD 2 expression and activity. RSV-induced inhibition of Nrf2 activation, due to proteasome-dependent degradation, causes a progressive decrease in the expression of a variety of AOEs involved in H2O2 detoxification leading to accumulation of highly reactive radicals, such as hydroxyl radical, and subsequent cellular damage (* autoxidation in presence of transition metals).
Mentions: The exact mechanism of decreased expression of AOEs during RSV infection, as well in the context of other viral respiratory infections, is largely unknown. Most of the AOE gene expression is regulated in part through ARE sequences and Nrf2 activity [30,67]. Transcription factor Nrf2 is an important redox-responsive protein that protects the cells from oxidative stress and injury (Reviewed in [16]). Nrf2-dependent AOE gene expression might be reduced by: (i) competition for binding to the ARE site - Bach1/small Maf protein complex or AP-1 family transcription factors like c-Fos and FRA1 can bind to ARE acting as a transcriptional repressor [67,68]; (ii) preventing Nrf2 activation through direct physical association - Activating transcription factor (ATF)3 or retinoic acid receptor α were shown to form inhibitory complexes with Nrf2, leading to displacement from ARE elements; (iii) interfering with recruitment of co activators, such as CBP, to the ARE site - NF-κB activation can lead to decreased availability of CBP and promote the recruitment of co repressors (histone deacetylases) at Nrf2-ARE site [67]; (iv) reduced nuclear levels, which can occur due to enhanced nuclear to cytoplasm efflux or increased Nrf2 degradation [8]. A recent study has shown that RSV infection in Nrf2−/− mice is more severe and associated with higher viral titers, augmented inflammation, enhanced mucus production and epithelial injury compared to Nrf2 wild type mice, indicating the protective role of Nrf2-ARE pathway against RSV infection [69]. RSV infection can indeed induced a progressive decrease in ARE-dependent gene transcription in A549 cells, carcinoma-derived type II-like airway epithelial cells, investigated using luciferase reporter gene assays (Figure 1A, left panel)[47]. A similar result was obtained when cells were infected with hMPV (Figure 1A, right panel). Reduced nuclear levels of Nrf2 was observed in both RSV infection (Figure 1B, left panel) [8] and hMPV infection (Figure 1B, right panel), together with increased nuclear levels of known ARE transcriptional repressors such as Bach1 and ATF3 (Casola A, unpublished observation) [47], suggesting a potential mechanism for viral-induced down regulation of AOE gene expression. As Nrf2 positively regulates its own gene transcription, reduced Nrf2 mRNA levels were observed in airway epithelial cells at late time point of RSV infection [8]. Our recent studies indicate that RSV infection is associated with Nrf2 deacetylation, likely due to RSV-induced upregulation of histone deacetylase (HDAC) activity, and increased degradation, which occurs through the ubiquitin-proteasome pathway. Blocking proteasome and class I HDAC activity, in particular HDAC 1 and 2, rescued Nrf2 activation and ARE-dependent gene expression during RSV infection (Casola A, unpublished observation). A summary of findings and a proposed model of RSV-induced oxidative stress in airway epithelial cells are depicted in Figure 2.

Bottom Line: They also reduce antioxidant enzyme (AOE) levels and/or activity, leading to unbalanced oxidative-antioxidant status and subsequent oxidative cell damage.While exposure to several pro-oxidant stimuli usually leads to Nrf2 activation and upregulation of AOE expression, respiratory viral infections are associated with inhibition of AOE expression/activity, which in the case of RSV and hMPV is associated with reduced Nrf2 nuclear localization, decreased cellular levels and reduced ARE-dependent gene transcription.Therefore, administration of antioxidant mimetics or Nrf2 inducers represents potential viable therapeutic approaches to viral-induced diseases, such as respiratory infections and other infections associated with decreased cellular antioxidant capacity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA.

ABSTRACT

Reactive oxygen species (ROS) formation is part of normal cellular aerobic metabolism, due to respiration and oxidation of nutrients in order to generate energy. Low levels of ROS are involved in cellular signaling and are well controlled by the cellular antioxidant defense system. Elevated levels of ROS generation due to pollutants, toxins and radiation exposure, as well as infections, are associated with oxidative stress causing cellular damage. Several respiratory viruses, including respiratory syncytial virus (RSV), human metapneumovirus (hMPV) and influenza, induce increased ROS formation, both intracellularly and as a result of increased inflammatory cell recruitment at the site of infection. They also reduce antioxidant enzyme (AOE) levels and/or activity, leading to unbalanced oxidative-antioxidant status and subsequent oxidative cell damage. Expression of several AOE is controlled by the activation of the nuclear transcription factor NF-E2-related factor 2 (Nrf2), through binding to the antioxidant responsive element (ARE) present in the AOE gene promoters. While exposure to several pro-oxidant stimuli usually leads to Nrf2 activation and upregulation of AOE expression, respiratory viral infections are associated with inhibition of AOE expression/activity, which in the case of RSV and hMPV is associated with reduced Nrf2 nuclear localization, decreased cellular levels and reduced ARE-dependent gene transcription. Therefore, administration of antioxidant mimetics or Nrf2 inducers represents potential viable therapeutic approaches to viral-induced diseases, such as respiratory infections and other infections associated with decreased cellular antioxidant capacity.

No MeSH data available.


Related in: MedlinePlus