https://orcid.org/0000-0002-2778-3530
-
Views
-
Cite
Cite
Pak-Hin Hinson Cheung, Zi-Wei Ye, Tak-Wang Terence Lee, Honglin Chen, Chi-Ping Chan, Dong-Yan Jin, PB1-F2 protein of highly pathogenic influenza A (H7N9) virus selectively suppresses RNA-induced NLRP3 inflammasome activation through inhibition of MAVS-NLRP3 interaction, Journal of Leukocyte Biology, Volume 108, Issue 5, Nov 2020, Pages 1655–1663, https://doi.org/10.1002/JLB.4AB0420-694R
Close - Share Icon Share
Abstract
Infection with seasonal as well as highly pathogenic avian influenza A virus (IAV) causes significant morbidity and mortality worldwide. As a major virulence factor, PB1-F2 protein of IAV affects the severity of disease through multiple mechanisms including perturbation of host innate immune response. Macrophages are known to phagocytose extracellular PB1-F2 protein aggregate, leading to hyperactivation of NLRP3 inflammasome and excessive production of IL-1β and IL-18. On the other hand, when expressed intracellularly PB1-F2 suppresses NLRP3 inflammasome maturation. How extracellular and intracellular PB1-F2 orchestrates to drive viral pathogenesis remains unclear. In this study, we demonstrated the suppression of NLRP3 inflammasome activation and IL-1β secretion by PB1-F2 of highly pathogenic influenza A (H7N9) virus in infected human monocyte-derived macrophages. Mechanistically, H7N9 PB1-F2 selectively mitigated RNA-induced NLRP3 inflammasome activation by inhibiting the interaction between NLRP3 and MAVS. Intracellular PB1-F2 of H7N9 virus did not affect extracellular PB1-F2-induced NLRP3 inflammasome maturation. In contrast, PB1-F2 of WSN laboratory strain of human IAV effectively suppressed IL-1β processing and secretion induced by various stimuli including NLRP3, AIM2, and pro-IL-1β. This subtype-specific effect of PB1-F2 on inflammasome activation correlates with the induction of a proinflammatory cytokine storm by H7N9 but not WSN virus. Our findings on selective suppression of MAVS-dependent activation of NLRP3 inflammasome by H7N9 PB1-F2 have implications in viral pathogenesis and antiviral development.
