Mammalian Innate Resistance to Highly Pathogenic Avian Influenza H5N1 Virus Infection Is Mediated through Reduced Proinflammation and Infectious Virus Release

Nelli, Rahul K.; Dunham, Stephen; Kuchipudi, Suresh V.; White, Gavin A.; Baquero-Pérez, Belinda; Chang, Pengxiang; Ghaemmaghami, Amir M.; Brookes, Sharon M.; Brown, Ian H.; Chang, Kin‐Chow

doi:10.1128/jvi.00244-12

Cited by 29 publications

(35 citation statements)

References 46 publications

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“…The elevation of SOCS1 and SOCS3 expression following influenza virus infection, as shown in the present studies (Fig. 5E) and in other literature (27,28,37), is likely to reflect the combined effect of a dynamic interaction between the host and the pathogen, resulting in the modulation of multiple signaling pathways infected with influenza viruses as indicated in the presence of 1% DMSO control or 1 mM apocynin for 24 h. Uninfected cells cultured in medium containing 1% DMSO were used as negative controls. ROS production (red) was detected by immunofluorescence with CellROX Deep Red reagent, and the total nuclei were shown with DAPI staining (blue).…”

Section: In Vitro Influenzamentioning

confidence: 64%

“…Apocynin assists the host by inhibiting ROS production, reducing phospho-FoxO3-Ser253, and increasing SOCS1 and SOCS3 expression. It is therefore not surprising that variable SOCS1 and SOCS3 mRNA and protein expression levels have been reported in human cells (27,28,37) following influenza virus infection given the fact that various cell types, influenza virus strains, and/or experimental conditions may influence outcomes. Future studies will need to be conducted in biologically relevant innate immune cells to fully characterize the role of FoxO and TAM receptors following influenza virus infection.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3

Lowther

Stambas

2015

J Virol

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Highly pathogenic avian influenza virus 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. Proinflammatory stimuli are known to induce intracellular reactive oxygen species by activating NADPH oxidase activity. We therefore hypothesized 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-pathogenicity avian influenza H5N3 virus (A/duck/Victoria/0305-2/2012), highly pathogenic avian influenza H5N1 virus (A/chicken/Vietnam/0008/2004), or low-pathogenicity avian influenza H7N9 virus (A/Anhui/1/2013). Quantitative real-time reverse transcriptase PCR showed that H5N1 and H7N9 viruses significantly stimulated cytokine (interleukin-6, beta interferon, 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 antiviral strategies (targeting viruses) as therapeutic agents to ameliorate disease severity in susceptible species. IMPORTANCEHighly pathogenic avian influenza virus infection causes severe morbidity and mortality in both humans and poultry. Widespread antiviral resistance necessitates the need for the development of additional novel therapeutic measures to modulate overactive host immune responses after infection. Disease severity following avian influenza virus infection can be attributed in part to hyperinduction of inflammatory mediators such as cytokines, chemokines, and reactive oxygen species. Our study shows that highly pathogenic avian influenza H5N1 virus and low-pathogenicity avian influenza H7N9 virus (both associated with human fatalities) promote inactivation of FoxO3 and downregulation 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 combinati...

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Section: In Vitro Influenzamentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3

Lowther

Stambas

2015

J Virol

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“…However, the overexpression of these cytokines causes a variety of complications and pathological injuries. Previous studies reported that TNF‐α and IL‐6 could aggravate the clinical symptoms and histopathological changes of influenza virus‐infected mice 41, 42. We hypothesize that SCG could stabilize the membrane of mast cells, which inhibits the release of inflammatory mediators and alleviates the inflammatory response induced by H5N1 infection.…”

Section: Discussionmentioning

confidence: 79%

The therapeutic effects of sodium cromoglycate against influenza A virus H5N1 in mice

Han

Wei

Zhang

et al. 2015

Influenza Resp Viruses

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ObjectivesTo identify the protective role of sodium cromoglycate in mice during influenza virus infection.DesignH5N1 virus‐infected mice were treated with the mast cell stabilizer sodium cromoglycate (SCG) to investigate its therapeutic effect.SampleThe nose, trachea and lungs from mice were collected.Main outcome measuresVirus replication and host responses were determined by plaque assay, quantitative PCR, immunohistochemistry, and histology.ResultsSCG‐treated mice survived better than did PBS‐treated mice after H5N1 virus infection. Mild pathological changes with fewer inflammatory cell infiltration and fewer virus antigens were observed in the nose, trachea, and lungs of SCG‐treated mice on days 3 and 5 post‐infection. However, no significant changes in viral load in the lungs were detected between SCG‐ and PBS‐treated mice. Furthermore, significantly decreased expression of interleukin‐6, tumor necrosis factor‐a, Toll‐like receptor 3, and TIR‐domain‐containing adapter‐inducing interferon‐b was detected in the lungs of SCG‐treated mice, and no higher expression of interferon‐c was detected.ConclusionThese results suggest that SCG has therapeutic roles in H5N1 virus‐infected mice by alleviating the inflammatory response rather than inhibition of viral replication in the lungs.

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“…However, an exaggerated inflammatory response is believed to contribute to H5N1-associated morbidity and mortality [52][53][54][55]. For example, the resistance of pigs to severe H5N1-mediated disease correlated with the lack of a strong pro-inflammatory response following infection [56][57][58]. Combined with evidence that macrophages support productive replication of some IAV strains, excessive cytokine production following H5N1 infection may be a result of productive virus replication in macrophages.…”

Section: Iav Replication and Hypercytokinemiamentioning

confidence: 99%

Influenza virus replication in macrophages: balancing protection and pathogenesis

Cline

Beck

Bianchini

2017

Journal of General Virology

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Macrophages are essential for protection against influenza A virus infection, but are also implicated in the morbidity and mortality associated with severe influenza disease, particularly during infection with highly pathogenic avian influenza (HPAI) H5N1 virus. While influenza virus infection of macrophages was once thought to be abortive, it is now clear that certain virus strains can replicate productively in macrophages. This may have important consequences for the antiviral functions of macrophages, the course of disease and the outcome of infection for the host. In this article, we review findings related to influenza virus replication in macrophages and the impact of productive replication on macrophage antiviral functions. A clear understanding of the interactions between influenza viruses and macrophages may lead to new antiviral therapies to relieve the burden of severe disease associated with influenza viruses.

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Mammalian Innate Resistance to Highly Pathogenic Avian Influenza H5N1 Virus Infection Is Mediated through Reduced Proinflammation and Infectious Virus Release

Cited by 29 publications

References 46 publications

Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3

Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3

The therapeutic effects of sodium cromoglycate against influenza A virus H5N1 in mice

Influenza virus replication in macrophages: balancing protection and pathogenesis

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