Type I IFN Triggers RIG-I/TLR3/NLRP3-dependent Inflammasome Activation in Influenza A Virus Infected Cells

Abstract

Influenza A virus (IAV) triggers a contagious and potentially lethal respiratory disease. A protective IL-1β response is mediated by innate receptors in macrophages and lung epithelial cells. NLRP3 is crucial in macrophages; however, which sensors elicit IL-1β secretion in lung epithelial cells remains undetermined. Here, we describe for the first time the relative roles of the host innate receptors RIG-I (DDX58), TLR3, and NLRP3 in the IL-1β response to IAV in primary lung epithelial cells. To activate IL-1β secretion, these cells employ partially redundant recognition mechanisms that differ from those described in macrophages. RIG-I had the strongest effect through a MAVS/TRIM25/Riplet–dependent type I IFN signaling pathway upstream of TLR3 and NLRP3. Notably, RIG-I also activated the inflammasome through interaction with caspase 1 and ASC in primary lung epithelial cells. Thus, NS1, an influenza virulence factor that inhibits the RIG-I/type I IFN pathway, strongly modulated the IL-1β response in lung epithelial cells and in ferrets. The NS1 protein derived from a highly pathogenic strain resulted in increased interaction with RIG-I and inhibited type I IFN and IL-1β responses compared to the least pathogenic virus strains. These findings demonstrate that in IAV-infected lung epithelial cells RIG-I activates the inflammasome both directly and through a type I IFN positive feedback loop.

AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality

“…8), in which AIM2-deficient AMs fail to produce IL-1b in response to IAV infection. Although in vitro inflammasome studies have shown that influenza infection can activate inflammasome in respiratory epithelial cells (23,49,50) and immune cells (51)(52)(53), our results reveal a central role for AMs in AIM2-related inflammasome regulation.…”

“…7 show that AIM2-deficient mice display steadily improved survival compared with WT mice after different doses and strains of IAV challenge. The survival rate in AIM2 2/2 mice doubled with the low dose of infection (0.5LD 50 ) and increased to 6-fold with the high dose of PR8 infection (50LD 50 ) at the end of observation (Fig. 7A).…”

“…Both viruses were propagated in MDCK cells as previously described (19); the concentration of viruses were titrated using plaque assay as previously described (17,19). In addition, LD 50 was determined according to Reed and Muench's method (20). For PR8, 1LD 50 equals 80 PFU; for CA07, 1LD 50 equals 10,000 PFU.…”

Inflammasomes and its importance in viral infections

“…Fascinatingly, these findings suggest the existence of dual roles for RIG-1 in the inflammasome and type 1 IFN pathways. A more recent study on primary human bronchial epithelial cells infected with influenza showed RIG-I-dependent priming of the NLRP3 inflammasome as well as direct RIG-I-mediated inflammasome activation [4]. Therefore, it can be assumed that RIG-I could activate its own inflammasome in response to some viruses, but its major functions in RIG-I-MAVS signalling and NLRP3 inflammasome activation are still the subject of debate, and further research is vitally needed.…”

“…This CARD-CARD interaction results in the dimerisation of MAVS in the mitochondria to form a protein complex called the MAVS signalosome, which enables the activation of NF-jB and the production of type I interferon (IFN). Once the innate immune system has been activated, it elicits the secretion of cytokines and chemokines, which subsequently induce the expression of adhesion molecules and costimulatory molecules to further activate the adaptive immune response [4][5][6][7][8][9][10][11].…”