Role of Hypercytokinemia in NF-κB p50-Deficient Mice after H5N1 Influenza A Virus Infection

ABSTRACT During H5N1 influenza virus infection, proinflammatory cytokines are markedly elevated in the lungs of infected hosts. The significance of this dysregulated cytokine response in H5N1-mediated pathogenesis remains to be determined. To investigate the influence of hypercytokinemia, or “cytokine storm,” a transgenic mouse technology was used. The classical NF-κB pathway regulates the induction of most proinflammatory cytokines. Deletion of the p50 subunit leads to a markedly reduced expression of the NF-κB-regulated cytokines and chemokines. Here we show that H5N1 influenza virus infection of this transgenic mouse model resulted in a lack of hypercytokinemia but not in altered pathogenesis.

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Host DNA released by NETosis in neutrophils exposed to seasonal H1N1 and highly pathogenic H5N1 influenza viruses

10.21203/rs.2.24164/v1 ◽

2020 ◽

Author(s):

Louisa L.Y. Chan ◽

John M. Nicholls ◽

J.S. Malik Peiris ◽

Yu Lung Lau ◽

Michael C.W. Chan ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

H1n1 Virus ◽

Influenza Virus Infection ◽

Alveolar Epithelium ◽

Influenza Viruses ◽

H5n1 Influenza Virus ◽

H5n1 Influenza ◽

Influenza H1n1

Abstract Background Neutrophil (Nϕ) is of the most abundant number in human immune system. During acute influenza virus infection, Nϕs are already active in the early phase of inflammation-a time in which clinical biopsy or autopsy material is not readily available. However, the role of Nϕ in virus infection is not well understood. Here, we studied the role of Nϕ in host defense during influenza A virus infection, specifically assessing if it contributes to the differential pathogenesis in H5N1 disease. Methods Nϕs were freshly isolated from healthy volunteers and subjected to direct influenza H1N1 and H5N1 virus infection in vitro . The ability of the naïve Nϕs to infiltrate from the basolateral to the apical phase of the influenza virus infected alveolar epithelium was assessed. The viral replication, innate immune responses and Neutrophil extracellular trap (NET) formation of Nϕs upon influenza virus infection were evaluated. Results Our results demonstrated that influenza virus infected alveolar epithelium allowed more Nϕs transmigration. Significantly more Nϕs migrated across the H5N1 influenza virus infected the epithelium than the counterpart infected by the seasonal influenza H1N1 virus infected. Nϕs were equally susceptible to H5N1 and H1N1 virus infection with similar viral gene transcription. Productive replication was observed in H5N1 infected Nϕs. Both H5N1 and H1N1 infected Nϕs induced cytokines and chemokines including TNF-α, IFN-β, CXCL10, MIP-1α and IL-8. This inferred a more intense inflammatory response posed by H5N1 than H1N1 virus. Strikingly, NADPH oxidase-independent NET formation was observed in H1N1 infected Nϕs at 6 hpi while no NET formation was observed upon H5N1 infection. Conclusion Our data is the first to demonstrate that NET formation is abrogated in H5N1 influenza virus infection. Its contribution to the differential severity of H5N1 disease requires further investigation.

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Host DNA released by NETosis in neutrophils exposed to seasonal H1N1 and highly pathogenic H5N1 influenza viruses

10.21203/rs.2.24164/v2 ◽

2020 ◽

Author(s):

Louisa L.Y. Chan ◽

John M. Nicholls ◽

J.S. Malik Peiris ◽

Yu Lung Lau ◽

Michael C.W. Chan ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Gene Transcription ◽

H1n1 Virus ◽

Influenza Virus Infection ◽

Alveolar Epithelium ◽

H5n1 Influenza Virus ◽

H5n1 Influenza ◽

Influenza H1n1

Abstract Background: Neutrophil is of the most abundant number in human immune system. During acute influenza virus infection, neutrophils are already active in the early phase of inflammation-a time in which clinical biopsy or autopsy material is not readily available. However, the role of neutrophil in virus infection is not well understood. Here, we studied the role of neutrophil in host defense during influenza A virus infection, specifically assessing if it contributes to the differential pathogenesis in H5N1 disease. Methods: Neutrophils were freshly isolated from healthy volunteers and subjected to direct influenza H1N1 and H5N1 virus infection in vitro. The ability of the naïve neutrophils to infiltrate from the basolateral to the apical phase of the influenza virus infected alveolar epithelium was assessed. The viral replication, innate immune responses and Neutrophil extracellular trap (NET) formation of neutrophils upon influenza virus infection were evaluated. Results: Our results demonstrated that influenza virus infected alveolar epithelium allowed more neutrophils transmigration. Significantly more neutrophils migrated across the H5N1 influenza virus infected the epithelium than the counterpart infected by the seasonal influenza H1N1 virus infected. Neutrophils were equally susceptible to H5N1 and H1N1 virus infection with similar viral gene transcription. Productive replication was observed in H5N1 infected neutrophils. H5N1 induced higher cytokine and chemokine gene transcription than H1N1 infected neutrophils, including TNF-α, IFN-β, CXCL10, MIP-1α and IL-8. This inferred a more intense inflammatory response posed by H5N1 than H1N1 virus. Strikingly, NADPH oxidase-independent NET formation was only observed in H1N1 infected neutrophils at 6 hpi while no NET formation was observed upon H5N1 infection.Conclusion: Our data is the first to demonstrate that NET formation is abrogated in H5N1 influenza virus infection and might contribute to the severity of H5N1 disease.

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Host DNA released by NETosis in neutrophils exposed to seasonal H1N1 and highly pathogenic H5N1 influenza viruses

Respiratory Research ◽

10.1186/s12931-020-01425-w ◽

2020 ◽

Vol 21 (1) ◽

Cited By ~ 1

Author(s):

Louisa L. Y. Chan ◽

John M. Nicholls ◽

J. S. Malik Peiris ◽

Yu Lung Lau ◽

Michael C. W. Chan ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Gene Transcription ◽

H1n1 Virus ◽

Influenza Virus Infection ◽

Alveolar Epithelium ◽

H5n1 Influenza Virus ◽

H5n1 Influenza ◽

Influenza H1n1

Abstract Background Neutrophil is of the most abundant number in human immune system. During acute influenza virus infection, neutrophils are already active in the early phase of inflammation - a time in which clinical biopsy or autopsy material is not readily available. However, the role of neutrophil in virus infection is not well understood. Here, we studied the role of neutrophil in host defense during influenza A virus infection, specifically assessing if it contributes to the differential pathogenesis in H5N1 disease. Methods Neutrophils were freshly isolated from healthy volunteers and subjected to direct influenza H1N1 and H5N1 virus infection in vitro. The ability of the naïve neutrophils to infiltrate from the basolateral to the apical phase of the influenza virus infected alveolar epithelium was assessed. The viral replication, innate immune responses and Neutrophil extracellular trap (NET) formation of neutrophils upon influenza virus infection were evaluated. Results Our results demonstrated that influenza virus infected alveolar epithelium allowed neutrophil transmigration. Significantly more neutrophils migrated across the H5N1 influenza virus infected the epithelium than the counterpart infected by the seasonal influenza H1N1 virus infected. Neutrophils were equally susceptible to H5N1 and H1N1 virus infection with similar viral gene transcription. Productive replication was observed in H5N1 infected neutrophils. H5N1 induced higher cytokine and chemokine gene transcription than H1N1 infected neutrophils, including TNF-α, IFN-β, CXCL10, MIP-1α and IL-8. This inferred a more intense inflammatory response posed by H5N1 than H1N1 virus. Strikingly, NADPH oxidase-independent NET formation was only observed in H1N1 infected neutrophils at 6 hpi while no NET formation was observed upon H5N1 infection. Conclusion Our data is the first to demonstrate that NET formation is abrogated in H5N1 influenza virus infection and might contribute to the severity of H5N1 disease.

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A critical role of IL-17 in modulating the B-cell response during H5N1 influenza virus infection

Cellular and Molecular Immunology ◽

10.1038/cmi.2011.38 ◽

2011 ◽

Vol 8 (6) ◽

pp. 462-468 ◽

Cited By ~ 43

Author(s):

Xiaohui Wang ◽

Chris CS Chan ◽

Min Yang ◽

Jun Deng ◽

Vincent KM Poon ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

B Cell ◽

Cell Response ◽

Critical Role ◽

Influenza Virus Infection ◽

H5n1 Influenza Virus ◽

H5n1 Influenza ◽

B Cell Response

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Oseltamivir-Ribavirin Combination Therapy for Highly Pathogenic H5N1 Influenza Virus Infection in Mice

Antiviral Research ◽

10.1016/j.antiviral.2007.01.020 ◽

2007 ◽

Vol 74 (3) ◽

pp. A31-A32 ◽

Cited By ~ 2

Author(s):

N ILYUSHINA ◽

R WEBSTER ◽

E GOVORKOVA

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Combination Therapy ◽

Influenza Virus Infection ◽

H5n1 Influenza Virus ◽

Highly Pathogenic ◽

H5n1 Influenza ◽

Pathogenic H5n1

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Cross-Reactive, Cell-Mediated Immunity and Protection of Chickens from Lethal H5N1 Influenza Virus Infection in Hong Kong Poultry Markets

Journal of Virology ◽

10.1128/jvi.75.6.2516-2525.2001 ◽

2001 ◽

Vol 75 (6) ◽

pp. 2516-2525 ◽

Cited By ~ 161

Author(s):

Sang Heui Seo ◽

Robert G. Webster

Keyword(s):

T Cells ◽

Influenza Virus ◽

Hong Kong ◽

Virus Infection ◽

Cellular Immunity ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

H5n1 Influenza Virus ◽

H9n2 Influenza Virus ◽

H5n1 Influenza

ABSTRACT In 1997, avian H5N1 influenza virus transmitted from chickens to humans resulted in 18 confirmed infections. Despite harboring lethal H5N1 influenza viruses, most chickens in the Hong Kong poultry markets showed no disease signs. At this time, H9N2 influenza viruses were cocirculating in the markets. We investigated the role of H9N2 influenza viruses in protecting chickens from lethal H5N1 influenza virus infections. Sera from chickens infected with an H9N2 influenza virus did not cross-react with an H5N1 influenza virus in neutralization or hemagglutination inhibition assays. Most chickens primed with an H9N2 influenza virus 3 to 70 days earlier survived the lethal challenge of an H5N1 influenza virus, but infected birds shed H5N1 influenza virus in their feces. Adoptive transfer of T lymphocytes or CD8+ T cells from inbred chickens (B2/B2) infected with an H9N2 influenza virus to naive inbred chickens (B2/B2) protected them from lethal H5N1 influenza virus. In vitro cytotoxicity assays showed that T lymphocytes or CD8+ T cells from chickens infected with an H9N2 influenza virus recognized target cells infected with either an H5N1 or H9N2 influenza virus in a dose-dependent manner. Our findings indicate that cross-reactive cellular immunity induced by H9N2 influenza viruses protected chickens from lethal infection with H5N1 influenza viruses in the Hong Kong markets in 1997 but permitted virus shedding in the feces. Our findings are the first to suggest that cross-reactive cellular immunity can change the outcome of avian influenza virus infection in birds in live markets and create a situation for the perpetuation of H5N1 influenza viruses.

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Progranulin aggravates pulmonary immunopathology during influenza virus infection

Thorax ◽

10.1136/thoraxjnl-2018-211916 ◽

2018 ◽

Vol 74 (3) ◽

pp. 305-308 ◽

Cited By ~ 6

Author(s):

Qin Luo ◽

Xingxing Yan ◽

Hongmei Tu ◽

Yibing Yin ◽

Ju Cao

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Inflammatory Diseases ◽

Influenza Virus Infection ◽

Epithelial Barrier ◽

Alveolar Epithelial ◽

Cytokines And Chemokines ◽

Deficient Mice ◽

Experimental Influenza

Progranulin (PGRN) exerts multiple functions in various inflammatory diseases. However, the role of PGRN in the pathogenesis of virus infection is unknown. Here, we demonstrated that PGRN production was up-regulated in clinical and experimental influenza, which contributed to the deleterious inflammatory response after influenza virus infection in mice. PGRN-deficient mice were protected from influenza virus-induced lung injury and mortality. Decreased mortality was associated with significantly reduced influx of neutrophils and monocytes/macrophages, release of cytokines and chemokines, and permeability of the alveolar–epithelial barrier without affecting viral clearance. Our findings suggest that PGRN exacerbates pulmonary immunopathology during influenza virus infection.

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