Vimentin-mediated activation of NLRP3 inflammasome in the mice brains infected with human Enterovirus 71

Abstract

Background: The severe infection of human enterovirus 71(EV71) is associated with childhood neuropathology. It has been reported that the infection of host cells by EV71 is dependent on the cell surface vimentin (VIM) as an attachment receptor for EV71. Moreover, VIM is identified as a key regulator of NLRP3 inflammasome which is responsible for pyroptosis and autophagy of host cells. Thus, VIM-induced activation of NLRP3 may contribute to the development of severe central nervous system (CNS) infection by EV71. However, the pathogenesis of EV71 CNS infection remains unknown. Therefore, it is important to elucidate the molecular mechanism of EV71 inducing VIM-associated activation of inflammasome in CNS infection. Methods & Materials: In order to explore whether VIM-mediated activation of inflammasome play an important role in the EV71 CNS infection, the VIM knockout mice (VIM-/-, 3 to 5 days old) and the wild-type (WT, same age) infected by using identified strain of EV71 isolated from a pharyngeal swab specimen of a 3-year-old male diagnosed as severe hand-foot-and-mouth disease were detected by RT-PCR. EV71-induced histopathological alterations were also observed. Then, the levels of caspase-1 and IL-1β were examined by ELISA and Western blot to determine the activation of NLRP3 in mice. Results: As shown in these results, the exhibited limb paralysis rates of VIM-/− mice and WT mice were (19 ± 4)% and (55.7 ± 7.7)% (P < 0.05, n = 30) respectively. The level of viral RNA in VIM-/− mice was lower as compared to that of WT mice (P < 0.05, n = 10), and the morphological changes and neurons death in brains of VIM-/− mice were less than that of WT mice. Furthermore, the level of IL-1β and caspase-1 in the CNS was significantly decreased in VIM-/− mice when compared to WT mice (P < 0.05, n = 5). Conclusion: In this report, we demonstrated for the first time that EV71 could activate NLRP3 inflammasome induced by VIM. These might lead to the development of EV71 CNS disease. (Acknowledgment: The study was supported by Grant from School of Public Health of Southern Medical University, China, No. GW201710 to H.C., Medical Science and Technology Research Fund of Guangdong, China, No. A2017298 to Q.X. H.Cao: Corresponding author)