Inflammasome Sensor NLRP1 Controls Rat Macrophage Susceptibility to Toxoplasma gondii

Kimberly M Cirelli,Gezahegn Gorfu,Mahtab Moayeri,Devorah Crown,Musa A Hassan,Stephen H Leppla,Michael E Grigg,Morton Printz,Jeroen P J Saeij,Christopher M Sassetti

doi:10.1371/journal.ppat.1003927

Abstract

Toxoplasma gondii is an intracellular parasite that infects a wide range of warm-blooded species. Rats vary in their susceptibility to this parasite. The Toxo1 locus conferring Toxoplasma resistance in rats was previously mapped to a region of chromosome 10 containing Nlrp1. This gene encodes an inflammasome sensor controlling macrophage sensitivity to anthrax lethal toxin (LT) induced rapid cell death (pyroptosis). We show here that rat strain differences in Toxoplasma infected macrophage sensitivity to pyroptosis, IL-1β/IL-18 processing, and inhibition of parasite proliferation are perfectly correlated with NLRP1 sequence, while inversely correlated with sensitivity to anthrax LT-induced cell death. Using recombinant inbred rats, SNP analyses and whole transcriptome gene expression studies, we narrowed the candidate genes for control of Toxoplasma-mediated rat macrophage pyroptosis to four genes, one of which was Nlrp1. Knockdown of Nlrp1 in pyroptosis-sensitive macrophages resulted in higher parasite replication and protection from cell death. Reciprocally, overexpression of the NLRP1 variant from Toxoplasma-sensitive macrophages in pyroptosis-resistant cells led to sensitization of these resistant macrophages. Our findings reveal Toxoplasma as a novel activator of the NLRP1 inflammasome in rat macrophages.

Highlights

Toxoplasma gondii is an obligate intracellular parasite, for which different host species or strains within a species display variable susceptibilities
We report here that rat macrophages from different inbred strains vary in sensitivity to Toxoplasma induced lysis
We find that NLRP1, an inflammasome sensor whose only known agonist is anthrax lethal toxin (LT), is activated by Toxoplasma infection

Summary

Introduction

Toxoplasma gondii is an obligate intracellular parasite, for which different host species or strains within a species display variable susceptibilities. Host innate immunity is known to play a critical role in susceptibility to infection. For example, resistance to Toxoplasma infection is critically dependent on the induction of IL-12, which subsequently induces IFN-c, the main mediator of toxoplasmicidal activities (for review, see [1]). Like humans, are quite resistant to Toxoplasma infection when compared to mice. The resistance of the Lewis (LEW) strain is characterized by total clearance of the parasite, failure to develop cysts and the absence of a strong antibody response. Fischer (CDF) and Brown Norway (BN) rats, are susceptible to chronic infection and develop transmissible cysts in their brain and muscle tissue [2,3]. Resistance in rats is a dominant trait and is linked to myeloid cell control of parasite proliferation [2,3]

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