NLRP3 deficiency exacerbates enterovirus infection in mice

Abstract

The role for the NOD-like receptor (NLR) P3 inflammasome in enterovirus infection remains controversial. Available data suggest that the NLRP3 inflammasome is protective against enterovirus A71 but detrimental to the host during coxsackievirus B3 (CVB3) infection. CVB3 is a common etiologic agent associated with myocarditis and pancreatitis. Previous findings on the role of NLRP3 in CVB3 were based primarily on indirect evidence. Here, we utilized NLRP3 knockout mice as well as immune and cardiac cells to investigate the direct interplay between CVB3 infection and NLRP3 activation. We demonstrated that NLRP3 knockout mice exhibited more severe disease phenotype after CVB3 infection (significantly higher virus titers), increased myocardial, and pancreatic damage, as well as markedly impaired cardiac function compared to nontransgenic control mice. We further showed that NLRP3 activity was enhanced during early stage of CVB3 infection, as evidenced by increased gene expression and/or secretion of IL-1β and caspase-1. Finally, we demonstrated that CVB3 inactivates the NLRP3 inflammasome by degrading NLRP3 and its upstream serine/threonine-protein kinase receptor-interacting protein 1/3 via the proteolytic activity of virus-encoded proteinases. Taken together, our results reveal the functional significance of NLRP3 in host antiviral immunity against CVB3 infection and the mechanisms by which CVB3 has evolved to counteract the host defense response.-Wang, C., Fung, G., Deng, H., Jagdeo, J., Mohamud, Y., Xue, Y. C., Jan, E., Hirota, J. A., Luo, H. NLRP3 deficiency exacerbates enterovirus infection in mice.

MicroRNA Modification of Coxsackievirus B3 Decreases Its Toxicity, while Retaining Oncolytic Potency against Lung Cancer

“…The pathological score was graded based on inflammation, necrosis, calcification, lesion area, and cellular vacuolization as previously described. 50…”

An overview of the immune mechanisms of viral myocarditis

“…On the contrary, increased susceptibility to CVB3 myocarditis was noted in animals deficient in TLR3 and TRIF (adapter protein for TLR3), as well as MDA‐5 and mitochondrial antiviral signaling (MAVS) protein occurring in association with skewed Th2 and Th17 responses, and reduced type I IFN secretion, suggesting their importance in disease protection 56,59,62,65 . Although animals lacking complement receptor (CR)1/CR2, TRIM21 (cytosolic ubiquitin ligase), a protein that has a synergistic function with the complement system, 127 and the IFN‐stimulated ubiquitin‐like protein ISG15 showed enhanced severity of myocarditis, 67,69,71 increased myocardial damage in NLRP3‐deficient mice suggests that the NLRP3 inflammasome activation may serve a protective function in CVB3 infection 73 . Because of the anti‐microbial properties of nitric oxide (NO), animals lacking NOS2 might have displayed increased CVB3 severity as predicted, 75 but a similar outcome in animals deficient in selenium and GPX‐1 (selenium‐dependent enzyme) may mean that anti‐oxidants also play disease‐protective roles 77,79 .…”

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

“…For example, the NLRP3 inflammasome plays a role in promoting hyperinflammation and disease during severe IAV infection (Allen et al, 2009; Ichinohe et al, 2009; McAuley et al, 2013; Kuriakose and Kanneganti, 2017). The NLRP3 inflammasome is also involved in EV71 and CVB3 infection (Wang et al, 2014, 2015, 2017, 2018a; Li et al, 2017; Miteva et al, 2018), suggesting a potential role for the NLRP3 inflammasome in viral pathogenesis.…”