Vibrio parahaemolyticus Effector Proteins Suppress Inflammasome Activation by Interfering with Host Autophagy Signaling

Abstract

Bacterial pathogens utilize pore-forming toxins or sophisticated secretion systems to establish infection in hosts. Recognition of these toxins or secretion system by nucleotide-binding oligomerization domain leucine-rich repeat proteins (NLRs) triggers the assembly of inflammasomes, the multiprotein complexes necessary for caspase-1 activation and the maturation of inflammatory cytokines such as IL-1β or IL-18. Here we demonstrate that both the NLRP3 and NLRC4 inflammasomes are activated by thermostable direct hemolysins (TDHs) and type III secretion system 1 (T3SS1) in response to V. parahaemolyticus infection. Furthermore, we identify T3SS1 secreted effector proteins, VopQ and VopS, which induce autophagy and the inactivation of Cdc42, respectively, to prevent mainly NLRC4 inflammasome activation. VopQ and VopS interfere with the assembly of specks in infected macrophages. These data suggest that bacterial effectors interfere with inflammasome activation and contribute to bacterial evasion from the host inflammatory responses.

Author Summary

V. parahaemolyticus is Gram-negative pathogen that causes a food poisoning in human. To date, a number of bacterial factors that play a role in V. parahaemolyticus virulence have been characterized, yet little is known about the host factors contributing to the disease process and susceptibility to these pathogens. IL-1β, in addition to TNF-α, is thought to be involved in inflammatory responses and disease development during infection with the pathogen, but the mechanisms of IL-1β production remain poorly defined. In this work we found that both the NLRP3 and NLRC4 inflammasomes are activated by thermostable direct hemolysins (TDHs) and type III secretion system 1 (T3SS1) in response to V. parahaemolyticus infection. The activated inflammasomes then triggers the activation of caspase-1, a cysteine protease that is essential for IL-1β processing and release. Furthermore, we identified T3SS1 secreted effector proteins, VopQ and VopS, which prevent mainly NLRC4 inflammasome activation. VopQ and VopS induce autophagy and the inactivation of Rho GTPases, including Cdc42, respectively, and these cellular events interfere with the assembly of specks, the platform of inflammasome activation. Collectively, T3SS1 effector-based suppression of inflammasome activation may provide important insights into bacterial strategies for evading inflammasome-mediated host immune responses.