title: Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii.
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.
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Cirelli
authors.affiliation: Molecular Parasitology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Gezahegn
authors.initials: G
authors.lastname: Gorfu
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Musa A
authors.initials: MA
authors.lastname: Hassan
authors.affiliation: Department of Pharmacology, University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Morton
authors.initials: M
authors.lastname: Printz
authors.affiliation: Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Devorah
authors.initials: D
authors.lastname: Crown
authors.affiliation: Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.affiliation: Molecular Parasitology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Grigg
authors.affiliation: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, United States of America.
authors.forename: Jeroen P J
authors.initials: JP
authors.lastname: Saeij
authors.affiliation: Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Moayeri
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease / Q000235:genetics; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000469:parasitology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D011919:Rats, Inbred Strains; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology*; D059467:Transcriptome
chemical_list: D058847:Inflammasomes; D009419:Nerve Tissue Proteins; C526260:Nlrp1a protein, rat