Hemagglutinin from the H5N1 Virus Activates Janus Kinase 3 to Dysregulate Innate Immunity

Highly pathogenic avian influenza viruses (HPAIVs) cause severe disease in humans. There are no effective vaccines or antiviral therapies currently available to control fatal outbreaks due in part to the lack of understanding of virus-mediated immunopathology. In our study, we used hemagglutinin (HA...

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Published in:PloS one Vol. 7; no. 2; p. e31721
Main Authors: Xu, Wei, Chen, Minhui, Ge, Nanhai, Xu, Jun
Format: Journal Article
Language:English
Published: United States Public Library of Science 16.02.2012
Public Library of Science (PLoS)
Subjects:
Animals
Antigens
Antiviral agents
Avian flu
Avian influenza
Avian influenza viruses
Biology
Cell cycle
Chemokines
Cytokine receptors
Cytokines
Development and progression
Disease
Ebola virus
Epithelial cells
Epithelial Cells - virology
Fatalities
Gene expression
Hemagglutinins
Hemagglutinins - immunology
Hemagglutinins - pharmacology
Hospitals
Immunity
Immunity, Innate - drug effects
Infections
Influenza
Influenza A Virus, H5N1 Subtype - immunology
Influenza vaccines
Inhibitors
Innate immunity
Janus kinase 3
Janus Kinase 3 - metabolism
Kinases
Laboratories
Lectins
Lung - virology
Lungs
Lymphocytes
Medicine
Mice
Mice, Knockout
Mutual fund industry
Outbreaks
Proteins
Psoriasis
Receptors
Respiratory diseases
Rheumatoid arthritis
Rodents
Signal transduction
Signal Transduction - immunology
Signaling
Transgenic animals
Vaccines
Viruses
China
ISSN:1932-6203, 1932-6203
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Summary:Highly pathogenic avian influenza viruses (HPAIVs) cause severe disease in humans. There are no effective vaccines or antiviral therapies currently available to control fatal outbreaks due in part to the lack of understanding of virus-mediated immunopathology. In our study, we used hemagglutinin (HA) of H5N1 virus to investigate the related signaling pathways and their relationship to dysregulated innate immune reaction. We found the HA of H5N1 avian influenza triggered an abnormal innate immune signalling in the pulmonary epithelial cells, through an unusual process involving activation of Janus kinase 3 (JAK3) that is exclusively associated with γc chain and is essential for signaling via all γc cytokine receptors. By using a selective JAK3 inhibitor and JAK3 knockout mice, we have, for the first time, demonstrated the ability to target active JAK3 to counteract injury to the lungs and protect immunocytes from acute hypercytokinemia -induced destruction following the challenge of H5N1 HA in vitro and in vivo. On the basis of the present data, it appears that the efficacy of selective JAK3 inhibition is likely based on its ability to block multiple cytokines and protect against a superinflammatory response to pathogen-associated molecular patterns (PAMPs) attack. Our findings highlight the potential value of selective JAK3 inhibitor in treating the fatal immunopathology caused by H5N1 challenge.
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Conceived and designed the experiments: JX. Performed the experiments: WX NG. Analyzed the data: WX MC NG JX. Contributed reagents/materials/analysis tools: JX. Wrote the paper: MC JX.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0031721