Dual role of Toxoplasma gondii ROP5 and ROP18 for NLRP3 inhibition

Abstract

Inflammasome activation leads release of IL-1{beta}, a proinflammatory cytokine that drives antimicrobial immune responses. Toxoplasma gondii has been shown to activate the NLRP3 inflammasome but the trigger has not yet been identified. Here we provide evidence that vacuolar disruption is a prerequisite for NLRP3 activation. T. gondii type I ROP5 and ROP18 protect the parasitophorous vacuolar membrane (PVM) and thereby inhibit inflammasome activation and IL-1{beta} release. Besides protection of the PVM, we demonstrate an additional function of ROP5 and ROP18 for NLRP3 inhibition. We demonstrate the molecular mechanism of this inhibition includes direct interaction with GBP5. In conclusion, T. gondii ROP5 and ROP18 inhibit IL-1{beta} production by protection of the intracellular replicative niche of the parasite and by actively subverting NLRP3 activation. Our findings provide further insight into the intricate mechanisms governing inflammasome activation and inhibition, enhancing our understanding of the complex dynamics during T. gondii infection. O_FIG O_LINKSMALLFIG WIDTH=155 HEIGHT=200 SRC="FIGDIR/small/558105v1_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@10a71b2org.highwire.dtl.DTLVardef@ae753eorg.highwire.dtl.DTLVardef@19365e7org.highwire.dtl.DTLVardef@74d9c_HPS_FORMAT_FIGEXP M_FIG C_FIG