The Bacterial T6SS Effector EvpP Prevents NLRP3 Inflammasome Activation by Inhibiting the Ca2+-Dependent MAPK-Jnk Pathway

Abstract

Inflammasome activation is an important innate immune defense mechanism against bacterial infection, and in return, bacteria express virulence determinants that counteract inflammasome activation. Many such effectors are secreted into host cells via specialized bacterial secretion systems. Here, the intracellular pathogenic bacterium Edwardsiella tarda was demonstrated to activate NLRC4 and NLRP3 inflammasomes via a type III secretion system (T3SS), and to inhibit NLRP3 inflammasome via a type VI secretion system (T6SS), indicating the antagonistic roles of these systems in inflammasome signaling. Furthermore, a non-VgrG T6SS effector, EvpP, was identified that significantly inhibited NLRP3 inflammasome activation. Subsequent studies revealed that EvpP significantly suppressed Jnk activation, thus impairing oligomerization of the inflammasome adaptor ASC. Moreover, EvpP counteracted cytoplasmic Ca increase, which works upstream of Jnk activation to regulate the NLRP3 inflammasome. Finally, EvpP-mediated inflammasome inhibition promoted bacterial colonization in vivo. This work expands our understanding of bacterial T6SS in counteracting host immune responses.

Rutaecarpine derivative R3 attenuates atherosclerosis via inhibiting NLRP3 inflammasome‐related inflammation and modulating cholesterol transport

“…We found that R3 markedly inhibited the NF-κB and MAPK pathway in vitro and in vivo, which are known activators of the NLRP3 inflammasome and have been recognized as atherogenic mechanisms, 26,[40][41][42] suggesting R3 could inhibit the priming signal of the NLRP3 inflammasome. Attenuation of NF-κB and MAPK pathways by R3 treatment would account for the lower expression of inflammatory cytokines detected in our study, including IL-6 and TNF-α.…”

Edwardsiella ictaluri evpP is required for colonisation of channel catfish ovary cells and necrosis in anterior kidney macrophages

“…However, evpP located right before the T6SS operon is transcriptionally regulated by the ferric uptake regulator (Fur) protein by binding to the fur box upstream of evpP promoter (Santander, Golden, Wanda, & Curtiss, 2012). In Edwardsiella piscicida, T6SS chaperone EvpC binds the disordered region of evpP that assists for translocation of evpP, particularly targeting the inflammasome activation in macrophages (H. Chen et al, 2017;Hu, Anand, Sivaraman, Leung, & Mok, 2014). Regulation of evpP in E. piscicida includes temperature, pH, Mg 2+ , inorganic phosphate, and iron concentration (Chakraborty et al, 2010;Chakraborty, Sivaraman, Leung, & Mok, 2011).…”

Dysregulated hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing

“…tarda ), an enteric pathogen infecting hosts from fish to human [28–29], was used to identify mutants that induced significantly increased pyroprosis in HeLa cells. Compared to the wild-type strain (EIB202), one of the mutants (0909I) greatly increased LDH release (Figs S1A and 1A) and IL-18 secretion (Fig 1B), accompanied by significantly induced caspase-4 activity (Fig 1C) in HeLa.…”