NLRP3 inflammasome activation by Foot-and-mouth disease virus infection mainly induced by viral RNA and non-structural protein 2B

Abstract

Foot-and-mouth disease virus (FMDV) is a positive-strand RNA virus of the family Picornaviridae. Early studies show that some viruses of Picornaviridae, such as EMCV and EV71, induce NLRP3 inflammasome activation. Our current study demonstrates that FMDV induces the secretion of caspase-1 and interleukin 1 beta (IL-1β), as well as activates the NLRP3 inflammasome in a doseand time-dependent manner. Meanwhile, NLRP3 inflammasome can suppress FMDV replication during virus infection. Both FMDV RNA and viroporin 2B stimulate NLRP3 inflammasome activation. FMDV RNA triggers NLRP3 inflammasome through p-NF-κB/p65 pathway not dependent on RIG-I inflammasome. FMDV 2B activates NLRP3 inflammasome through elevation of intracellular ion, but not dependent on mitochondrial reactive oxygen species (ROS) and lysosomal cathepsin B. It further demonstrates that 2B viroporin activates NLRP3 inflammasome and induces IL-1β in mice, which enhances the specific immune response against FMDV as an ideal self-adjuvant for FMD VLPs vaccine in guinea pigs. The results reveal a series of regulations between NLRP3 inflammasome complex and FMDV. Amino acids 140-145 of 2B is essential for forming an ion channel. By mutating the amino acid and changing the hydrophobic properties, the helical transmembrane region of the viroporin 2B is altered, so that the 2B is insufficient to trigger the activation of NLRP3 inflammasome. This study demonstrates the functions of FMDV RNA and 2B viroporin activate NLRP3 inflammasome and provides some useful information for the development of FMD vaccine self-adjuvant, which is also helpful for the establishment of effective prevention strategies by targeting NLRP3 inflammasome.

Viroporins and inflammasomes: A key to understand virus-induced inflammation

“…Another member of the picornaviridae family is foot-and-mouth disease virus (FMDV). Both FMDV RNA and viroporin 2B were shown to stimulate NLRP3 inflammasome activation by elevation of intracellular ion, but not dependent on mitochondrial reactive oxygen species (ROS) and lysosomal cathepsin B [107].…”

Role of Mitochondria in Viral Infections

“…RIG-I-mediated activation of NF-κB requires MAVS and a complex of CARD9 and Bcl-10 adaptor proteins [ 88 ]. RIG-I also binds to the adaptor protein ASC and stimulates caspase-1-dependent inflammasome activation by a mechanism independent of MAVS, which suggests that RIG-I activates the inflammasome in response to certain RNA viruses [ 88 , 89 , 90 ].…”

Activation and Inhibition of the NLRP3 Inflammasome by RNA Viruses

“…The FMDV 2B protein activates NLRP3 inflammasomes by decreasing [K + ] cyt and increasing [Ca 2+ ] cyt , causing the release of IL-1β. 152 This evidence shows that the FMDV 2B protein can activate NLRP3 inflammasomes via ion channel formation in a ROS-independent manner.…”

“… 151 The 2B protein of FMDV, a non-structural protein, can induce NLRP3 activation and IL-1β secretion. 152 It has been reported that signal 2 for NLRP3 activation in response to FMDV infection involves K + efflux and Ca 2+ influx but is ROS and cathepsin B independent. The 2B protein can change the membrane permeability, causing an imbalance regarding [Ca 2+ ] cyt in the host cell.…”