title: Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1.
abstract: Anthrax lethal toxin (LT) is a bipartite protease-containing toxin and a key virulence determinant of Bacillus anthracis. In mice, LT causes the rapid lysis of macrophages isolated from certain inbred strains, but the correlation between murine macrophage sensitivity and mouse strain susceptibility to toxin challenge is poor. In rats, LT induces a rapid death in as little as 37 minutes through unknown mechanisms. We used a recombinant inbred (RI) rat panel of 19 strains generated from LT-sensitive and LT-resistant progenitors to map LT sensitivity in rats to a locus on chromosome 10 that includes the inflammasome NOD-like receptor (NLR) sensor, Nlrp1. This gene is the closest rat homolog of mouse Nlrp1b, which was previously shown to control murine macrophage sensitivity to LT. An absolute correlation between in vitro macrophage sensitivity to LT-induced lysis and animal susceptibility to the toxin was found for the 19 RI strains and 12 additional rat strains. Sequencing Nlrp1 from these strains identified five polymorphic alleles. Polymorphisms within the N-terminal 100 amino acids of the Nlrp1 protein were perfectly correlated with LT sensitivity. These data suggest that toxin-mediated lethality in rats as well as macrophage sensitivity in this animal model are controlled by a single locus on chromosome 10 that is likely to be the inflammasome NLR sensor, Nlrp1.
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Newman
authors.forename: Morton P
authors.initials: MP
authors.lastname: Printz
authors.forename: Shihui
authors.initials: S
authors.lastname: Liu
authors.forename: Devorah
authors.initials: D
authors.lastname: Crown
authors.forename: Laura
authors.initials: L
authors.lastname: Breen
authors.forename: Sharmina
authors.initials: S
authors.lastname: Miller-Randolph
authors.forename: Pamela
authors.initials: P
authors.lastname: Flodman
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.forename: Mahtab
authors.initials: M
authors.lastname: Moayeri
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000881:Anthrax / Q000235:genetics* / Q000276:immunology / Q000401:mortality*; D000942:Antigens, Bacterial / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism*; D002478:Cells, Cultured; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D020022:Genetic Predisposition to Disease; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D017434:Protein Structure, Tertiary; D051381:Rats; D011914:Rats, Inbred BN; D020303:Rats, Inbred Dahl; D011916:Rats, Inbred F344; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D009419:Nerve Tissue Proteins; C526260:Nlrp1a protein, rat; C030325:anthrax toxin