Highly pathogenic avian influenza H5N1 virus delays apoptotic responses via activation of STAT3

Abstract

Background: Highly pathogenic avian influenza (HPAI) H5N1 virus continues to pose pandemic threat, but there is a lack of understanding of its pathogenesis. We compared the apoptotic responses triggered by HPAI and low pathogenic influenza viruses. Method: We compared the induction of apoptosis by HPAI H5N1 viruses, a low pathogenic seasonal H1N1 virus and an avian H9N2 virus. This study used physiologically relevant respiratory epithelial cells—human bronchial epithelial and alveolar epithelial cells. The mechanism of apoptosis induction by two representative viruses was further investigated in terms of the activation of caspase-3, -8, and -9 using human alveolar epithelial cells. The role of TRAIL and STAT3 in apoptosis induction was evaluated. Results: We demonstrated that H5N1 viruses delayed apoptosis in primary human bronchial and alveolar epithelial cells (AECs) compared to H1N1 virus. Both caspase-8 and -9 were activated by H5N1 and H1N1 viruses in AECs, while H5N1 differentially up-regulated TRAIL. H5N1-induced apoptosis was reduced by TRAIL receptor silencing. More importantly, STAT3 knock-down increased apoptosis by H5N1 infection suggesting that H5N1 virus delays apoptosis through activation of STAT3. Conclusion: Taken together, we demonstrated that STAT3 is involved in H5N1-delayed apoptosis compared to H1N1. Since delay in apoptosis prolongs the duration of virus replication and production of pro-inflammatory cytokines and TRAIL from H5N1-infected cells, which contribute to orchestrate cytokine storm and tissue damage, our results suggest that STAT3 may play a previously unsuspected role in H5N1 pathogenesis.