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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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-03-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1003927 |
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| 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 |
| collection | DOAJ |
| 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 |
| id | doaj-art-08ffeadd52ba4b23a88d6edb3374c793 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2014-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-08ffeadd52ba4b23a88d6edb3374c7932025-08-20T02:34:09ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-03-01103e100392710.1371/journal.ppat.1003927Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii.Kimberly M CirelliGezahegn GorfuMusa A HassanMorton PrintzDevorah CrownStephen H LepplaMichael E GriggJeroen P J SaeijMahtab MoayeriToxoplasma 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.https://doi.org/10.1371/journal.ppat.1003927 |
| spellingShingle | 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. PLoS Pathogens |
| title | 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_short | Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii. |
| title_sort | inflammasome sensor nlrp1 controls rat macrophage susceptibility to toxoplasma gondii |
| url | https://doi.org/10.1371/journal.ppat.1003927 |
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