Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii.

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 inf...

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Autores principales:	Kimberly M Cirelli, Gezahegn Gorfu, Musa A Hassan, Morton Printz, Devorah Crown, Stephen H Leppla, Michael E Grigg, Jeroen P J Saeij, Mahtab Moayeri
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/08ffeadd52ba4b23a88d6edb3374c793
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spelling	oai:doaj.org-article:08ffeadd52ba4b23a88d6edb3374c7932021-11-18T06:06:51ZInflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii.1553-73661553-737410.1371/journal.ppat.1003927https://doaj.org/article/08ffeadd52ba4b23a88d6edb3374c7932014-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24626226/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Toxoplasma 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.Kimberly M CirelliGezahegn GorfuMusa A HassanMorton PrintzDevorah CrownStephen H LepplaMichael E GriggJeroen P J SaeijMahtab MoayeriPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 10, Iss 3, p e1003927 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Kimberly M Cirelli Gezahegn Gorfu Musa A Hassan Morton Printz Devorah Crown Stephen H Leppla Michael E Grigg Jeroen P J Saeij Mahtab Moayeri Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii.
description	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.
format	article
author	Kimberly M Cirelli Gezahegn Gorfu Musa A Hassan Morton Printz Devorah Crown Stephen H Leppla Michael E Grigg Jeroen P J Saeij Mahtab Moayeri
author_facet	Kimberly M Cirelli Gezahegn Gorfu Musa A Hassan Morton Printz Devorah Crown Stephen H Leppla Michael E Grigg Jeroen P J Saeij Mahtab Moayeri
author_sort	Kimberly M Cirelli
title	Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii.
title_short	Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii.
title_full	Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii.
title_fullStr	Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii.
title_full_unstemmed	Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii.
title_sort	inflammasome sensor nlrp1 controls rat macrophage susceptibility to toxoplasma gondii.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/08ffeadd52ba4b23a88d6edb3374c793
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Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii.

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