Rabies Virus Is Recognized by the NLRP3 Inflammasome and Activates Interleukin-1β Release in Murine Dendritic Cells

Abstract

Inflammasome activation is important for the development of an effective host defense against many pathogens, including RNA viruses. However, the mechanism by which the inflammasome recognizes RNA viruses and its role in rabies virus (RABV) pathogenicity and immunogenicity remain poorly defined. To determine the function of the inflammasome in response to RABV infection, we infected murine bone marrow-derived dendritic cells (BMDCs) with RABV. Our results indicate that the infection of BMDCs with RABV induces both the production of pro-interleukin-1␤ (pro-IL-1␤) and its processing, resulting in the secretion of active IL-1␤ through activation of the NLRP3-, ASC-, and caspase-1-dependent inflammasome. As previously shown for the induction of type I interferon by RABV, the induction of pro-IL-1␤ also depends upon IPS-1. We demonstrate that both the production of pro-IL-1␤ and activation of the inflammasome require viral replication. We also demonstrate that increased viral replication in BMDCs derived from IFNAR-deficient mice resulted in significantly more IL-1␤ release. Additionally, IL-1 receptor-deficient mice show an increase in RABV pathogenicity. Taken together, these results indicate an important role of the inflammasome in innate immune recognition of RABV.

EV71 3D Protein Binds with NLRP3 and Enhances the Assembly of Inflammasome Complex

“…The best-characterized inflammasomes is the NLRP3 inflammasome, which activates the maturation of IL-1β through promoting the cleavage of pro-Casp-1 to generate active subunits, p20 and p10 [14]. NLRP3 inflammasome regulates innate immunity in responding to several RNA viruses, including influenza A virus (IAV) [33], encephalomyocarditis virus (EMCV) and vesicular stomatitis virus (VSV) [34], measles virus (MV) [35], myxoma virus (MYXV) [36], adenovirus (Ad) [37], West Nile virus (WNV) [38], Rabies virus (RV) [39], Herpes simplex virus 1 (HSV-1) [40], Rift valley fever virus (RVFV) [41], human T-lymphotropic virus 1 (HTLV-1) [42], and EV71 [16]. However, the mechanisms underlying the assembly of NLRP3 inflammasome regulated by viruses have not been reported.…”

Rift Valley fever virus infection induces activation of the NLRP3 inflammasome

“…The NSs del strain was generated on the rMP-12 backbone and lacks the gene encoding the NSs virulence factor (25). Dendritic cells had previously been identified to be potent producers of IL-1β in response to many viruses (17, 21). While macrophages have also been shown to support inflammasome activation in response to viruses, we chose to focus our efforts on dendritic cells (14, 21).…”

“…RNA viruses such as respiratory syncytial virus, encephalomyocarditis virus, influenza, and rabies virus have been shown to induce activation of the NLRP3 inflammasome (14–17). Additionally, inflammasomes can be found outside of the NLR family.…”

Inflammasome control of viral infection

“…Pothlichet et al [68] reported that primary human bronchial epithelial cells (NHBEs) infected with influenza A virus resulted in RIG-I dependent priming of the NLRP3 inflammasome as well as direct RIG-I mediated inflammasome activation. Additionally, three separate reports demonstrated that MAVS associates with NLRP3 and either recruits NLRP3 to mitochondria or is essential in upregulating NLRP3 and pro-IL-1β, thus priming the inflammasome [60,69–71]. MAVS may further facilitate NLRP3 inflammasome activation through the formation of prion-like oligomers that result in membrane damage and subsequent NLRP3 inflammasome activation [72,73].…”