Influenza virus activates inflammasomes via its intracellular M2 ion channel

Takeshi Ichinohe, et al. 2010. Nat. Immunol. 11, 404-410

Speaker: Ting-Jing Shen (沈庭靚)                         Time: 14:10~15:00, Sep, 15, 2010

Commentator: Dr. Pei-Jane Tsai (蔡佩珍 老師)          Place: Room 601

Abstract:

Influenza virus, a single-stranded RNA virus, causes severe epidemic illness annually. Previous studies have shown that influenza virus infection caused Nod-like receptor protein 3 (NLRP3)-inflammasome activation to release the pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18 both in macrophages and dendritic cells¹. The NLRP3-inflammasome is composed of NLRP3, ASC, and caspase-1, and is activated by two signals, toll-like receptor (TLR)-mediated signaling and ion efflux-induced membrane disarrangement. However, the mechanisms of how influenza virus activates NLRP3-inflammasome to release mature IL-1b are unknown. This study revealed that the TLR7 recognition was required for the stimulation of pro-IL-1b synthesis but failed to induce the production of mature IL-1b due to the lack of activated caspase-1 in influenza virus infection. They found that the M2 protein, a proton-specific ion channel of influenza virus², was able to activate caspase-1 that further cleaves pro-IL-1b to generate IL-1b by disturbing the ionic concentration both in bone marrow-derived macrophages dendritic cells. In addition, the localization of M2 protein in trans-Golgi network and the acidification of Golgi compartment were required for the induction of NLRP3-inflammasome. Collectively, influenza virus activated NLRP3-inflammasome through M2-mediated disturbance of ion efflux in acidified Golgi. This report reveals a previously uncharacterized role of influenza M2 ion channel on pathogen-recognition pathway and provides a new direction of antiviral therapies.

References:

1.      Allen, I.C. et al. 2009. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity. 30:556-565.

2.      Pinto, L.H. et al. 2006. The M2 proton channels of influenza A and B viruses. J. Biol. Chem. 281:8997-9000.