Hijacking the NLRP3 inflammasome: a mechanism underlying viral respiratory disease?

Abstract

In contrast to highly specific sensor molecules of the innate immune system, the NLRP3 receptor detects a broad variety of danger signals including pathogens. Sensing triggers intracellular NLRP3 inflammasome complex assembly to induce an inflammatory response with the primary aim to eliminate pathogens. However, several of them have developed distinct strategies to hijack NLRP3-dependent immunity. In this issue of EMBO Reports, Zhang and colleagues demonstrate that reovirus infection of airway epithelial cells promotes EphA2-dependent phosphorylation of NLRP3 that impedes the recruitment of other inflammasome components necessary for its activation [1]. This potentially uncovers a mechanism that may lead to reduced viral clearance in the lung, eventually contributing to life-threatening respiratory disease.

Figure 1. Reovirus hijacks NLRP3 inflammasome activation through EphA2‐mediated inhibitory phosphorylation of NLRP3

In wild‐type AECs (left panel), reovirus activates EphA2, which phosphorylates tyrosine 132 of NLRP3, preventing the assembly of the mature inflammasome, while in EphA2 knockout cells (right panel), reovirus activates NLRP3, which recruits ASC and pro‐CASP1 to assemble the mature inflammasome, resulting in the maturation and secretion of IL‐1β and IL‐18 and induction of pyroptosis.