tetano
Editor, Senior Moderator
J Virol. 2014 Dec 17. pii: JVI.03529-14. [Epub ahead of print]
[h=1]Inhibition of reactive oxygen species production ameliorates inflammation induced by influenza A viruses via up-regulation of SOCS1 and SOCS3.[/h] Ye S[SUP]1[/SUP], Lowther S[SUP]2[/SUP], Stambas J[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Highly pathogenic avian influenza infection is associated with severe mortality in both humans and poultry. The mechanisms of disease pathogenesis and immunity are poorly understood although recent evidence suggests that cytokine/chemokine dysregulation contributes to disease severity following H5N1 infection. Influenza A virus infection causes a rapid influx of inflammatory cells, resulting in increased reactive oxygen species production, cytokine expression and acute lung injury. Pro-inflammatory stimuli are known to induce intracellular reactive oxygen species by activating NADPH oxidase activity. We therefore hypothesised that inhibition of this activity would restore host cytokine homeostasis following avian influenza virus infection. A panel of airway epithelial and immune cells from mammalian and avian species were infected with A/Puerto Rico/8/1934 H1N1 virus, low pathogenic avian influenza H5N3 virus (A/duck/Victoria/0305-2/2012), highly pathogenic avian influenza H5N1 virus (A/chicken/Vietnam/0008/2004), or low pathogenic avian influenza H7N9 virus (A/Anhui/1/2013). Quantitative real-time reverse transcriptase PCR showed that H5N1 and H7N9 viruses significantly stimulated cytokine (IL-6, IFN-β, CXCL10 and CCL5) production. Among the influenza-induced cytokines, CCL5 was identified as a potential marker for overactive immunity. Apocynin, a Nox2 inhibitor, inhibited influenza-induced cytokines and reactive oxygen species production, although viral replication was not significantly altered in vitro. Interestingly, apocynin treatment significantly increased influenza virus-induced mRNA and protein expression of SOCS1 and SOCS3, enhancing negative regulation of cytokine signaling. These findings suggest that apocynin or its derivatives (targeting host responses) could be used in combination with anti-viral strategies (targeting viruses), as therapeutic agents to ameliorate disease severity in susceptible species.
[h=4]IMPORTANCE:[/h] Highly pathogenic avian influenza virus infection causes severe morbidity and mortality in both humans and poultry. Wide-spread antiviral resistance necessitates the need for the development of additional novel therapeutic measures to modulate overactive host immune responses following infection. Disease severity following avian influenza virus infection can be attributed in part to hyper-induction of inflammatory mediators such as cytokines, chemokines and reactive oxygen species. Our study shows that highly pathogenic avian influenza H5N1 virus and low pathogenic avian influenza H7N9 virus (both associated with human fatalities) promote inactivation of FoxO3 and down-regulation of the TAM receptor tyrosine kinase, Tyro3, leading to augmentation of the inflammatory cytokine response. Inhibition of influenza-induced reactive oxygen species with apocynin activated FoxO3 and stimulated SOCS1 and SOCS3 proteins, restoring cytokine homeostasis. We conclude that modulation of host immune responses with antioxidant and/or anti-inflammatory agents in combination with antiviral therapy may have important therapeutic benefits.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID: 25520513 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25520513
[h=1]Inhibition of reactive oxygen species production ameliorates inflammation induced by influenza A viruses via up-regulation of SOCS1 and SOCS3.[/h] Ye S[SUP]1[/SUP], Lowther S[SUP]2[/SUP], Stambas J[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Highly pathogenic avian influenza infection is associated with severe mortality in both humans and poultry. The mechanisms of disease pathogenesis and immunity are poorly understood although recent evidence suggests that cytokine/chemokine dysregulation contributes to disease severity following H5N1 infection. Influenza A virus infection causes a rapid influx of inflammatory cells, resulting in increased reactive oxygen species production, cytokine expression and acute lung injury. Pro-inflammatory stimuli are known to induce intracellular reactive oxygen species by activating NADPH oxidase activity. We therefore hypothesised that inhibition of this activity would restore host cytokine homeostasis following avian influenza virus infection. A panel of airway epithelial and immune cells from mammalian and avian species were infected with A/Puerto Rico/8/1934 H1N1 virus, low pathogenic avian influenza H5N3 virus (A/duck/Victoria/0305-2/2012), highly pathogenic avian influenza H5N1 virus (A/chicken/Vietnam/0008/2004), or low pathogenic avian influenza H7N9 virus (A/Anhui/1/2013). Quantitative real-time reverse transcriptase PCR showed that H5N1 and H7N9 viruses significantly stimulated cytokine (IL-6, IFN-β, CXCL10 and CCL5) production. Among the influenza-induced cytokines, CCL5 was identified as a potential marker for overactive immunity. Apocynin, a Nox2 inhibitor, inhibited influenza-induced cytokines and reactive oxygen species production, although viral replication was not significantly altered in vitro. Interestingly, apocynin treatment significantly increased influenza virus-induced mRNA and protein expression of SOCS1 and SOCS3, enhancing negative regulation of cytokine signaling. These findings suggest that apocynin or its derivatives (targeting host responses) could be used in combination with anti-viral strategies (targeting viruses), as therapeutic agents to ameliorate disease severity in susceptible species.
[h=4]IMPORTANCE:[/h] Highly pathogenic avian influenza virus infection causes severe morbidity and mortality in both humans and poultry. Wide-spread antiviral resistance necessitates the need for the development of additional novel therapeutic measures to modulate overactive host immune responses following infection. Disease severity following avian influenza virus infection can be attributed in part to hyper-induction of inflammatory mediators such as cytokines, chemokines and reactive oxygen species. Our study shows that highly pathogenic avian influenza H5N1 virus and low pathogenic avian influenza H7N9 virus (both associated with human fatalities) promote inactivation of FoxO3 and down-regulation of the TAM receptor tyrosine kinase, Tyro3, leading to augmentation of the inflammatory cytokine response. Inhibition of influenza-induced reactive oxygen species with apocynin activated FoxO3 and stimulated SOCS1 and SOCS3 proteins, restoring cytokine homeostasis. We conclude that modulation of host immune responses with antioxidant and/or anti-inflammatory agents in combination with antiviral therapy may have important therapeutic benefits.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID: 25520513 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25520513