Interactions Between Enteroviruses and the Inflammasome: New Insights Into Viral Pathogenesis

Abstract

Enteroviruses (EVs) have emerged a substantial threat to public health. EVs infection range from mild to severe disease, including mild respiratory illness, diarrhea, poliomyelitis, hand, foot, and mouth disease, aseptic meningitis, and encephalitis. In the Asia-Pacific region, for example, one of the best studied enterovirus 71 (EV71) has been associated with pandemics of hand, foot, and mouth disease (HFMD) in children, particularly those under the age of five. Serious HFMD cases are associated with neurological complications, such as aseptic meningitis, acute flaccid paralysis, brainstem encephalitis, and have been associated with as many as 1000s of deaths in children and infants from 2008 to 2017, in China. More than 90% of laboratory confirmed deaths due to HMFD are associated with EV71. However, little is known about the pathogenesis of EVs. Studies have reported that EVs-infected patients with severe complications show elevated serum concentrations of IL-1β. The secretion of IL-1β is mediated by NLRP3 inflammasome during EV71 and CVB3 infection. Enteroviruses 2B and 3D proteins play an important role in activation of NLRP3 inflammasome, while 3C and 2A play important roles in antagonizing the activation of NLRP3 and the secretion of IL-1β. In this review, we summarize current knowledge regarding the molecular mechanisms that underlie the activation and regulation of the NLRP3 inflammasome, particularly how viral proteins regulate NLRP3 inflammasome activation. These insights into the relationship between the NLRP3 inflammasome and the pathogenesis of EVs infection may ultimately inform the development of novel antiviral drugs.

Keywords: 2A and 3C; 2B and 3D; NLRP3 inflammasome; enteroviruses; pathogenesis.

FIGURE 1

EV71 regulates the NLRP3 inflammasome. During EV71 infection, viral RNA is detected by PRRs and NF-κB is activated, which leaded to the upregulation of NLRP3, pro-IL-1β, and pro-IL-18. Meanwhile, EV71 3D protein binds to the LRR domain of NLRP3, which subsequently interacts with the PYRIN domain of ASC to form a “3D-NLRP3-ASC” ring-like inflammasome complex (Wang et al., 2017). The CARD domain of pro-caspase-1 then interacts with the CARD domain of ASC to form activated caspase-1, which mediates the maturation and secretion of IL-1β and IL-18. EMCV 2B was sufficient to activate NLRP3 inflammasome. 2B of poliovirus and EV71 also induces the NLRP3 redistribution (Ito et al., 2012). The EV71 and CVB3 3C proteases and EV71 2A can inhibit NLRP3 inflammasome activation by cleaving NLRP3 (Wang et al., 2015, 2018a). Activated caspase-1 also cleaves GSDMD at D275-G276 to produce N_1-275-GSDMD, which is sufficient to induce pyroptosis by embedding itself directly within the membrane and inducing pore formation to release IL-1β. EV71 3C can cleave GSDMD at the Q193-G194 pair to produce N_1-193-GSDMD, which does not induce cell pyroptosis (Lei et al., 2017).