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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Vydané v:	PloS one Ročník 7; číslo 2; s. e31721
Hlavní autori:	Xu, Wei, Chen, Minhui, Ge, Nanhai, Xu, Jun
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Public Library of Science 16.02.2012 Public Library of Science (PLoS)
Predmet:	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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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 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