Abstract
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.
Highlights
Pathogenic avian influenza (HPAI) is an extremely contagious, multi-organ systemic disease [1]
The IL-8 chemokine is produced by bronchial epithelial cells and may function in the pathogenesis of acute respiratory distress syndrome (ARDS) [9], which may be relevant to H5N1 influenza, as progression to respiratory failure is associated with the development of ARDS [10,11]
We tested if the recombinant HA could induce activation of JAK/STAT and NF-kB signal pathways, which are responsible for transcriptional activation of chemokines/cytokines genes and lead to an innate immune response against pathogens
Summary
Pathogenic avian influenza (HPAI) is an extremely contagious, multi-organ systemic disease [1]. Clinical observations indicated that acute lung injury and multiple organ dysfunction were the direct causes of death in H5N1-infected humans [4,5]. Laboratory findings revealed low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in H5N1-infected individuals, in those who died. Levels of IP-10, MIG and MCP-1 (chemoattractants of monocytes and macrophages that are produced in bronchial epithelial cells and alveolar macrophages [6,7,8]) were elevated in patients with avian and human subtypes of influenza but were higher in H5N1-infected individuals and high in those who died [6]. The clinical and pathological features in H5N1-infected humans and animal models suggest that high levels of viral replication combined with early robust host responses play a key role in pneumonia severity and outcome [6,10,11,12,13,14,15,16]
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