Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1

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...

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Bibliographic Details
Published in:PLoS pathogens 2010-05, Vol.6 (5), p.e1000906-e1000906
Main Authors: Newman, Zachary L, Printz, Morton P, Liu, Shihui, Crown, Devorah, Breen, Laura, Miller-Randolph, Sharmina, Flodman, Pamela, Leppla, Stephen H, Moayeri, Mahtab
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Anthrax
Anthrax - genetics
Anthrax - immunology
Anthrax - mortality
Antigens, Bacterial - metabolism
Apoptosis
Bacillus anthracis
Bacterial toxins
Bacterial Toxins - metabolism
Causes of
Cells, Cultured
Chromosome Mapping
Chromosomes, Mammalian
Development and progression
Disease Models, Animal
Disease susceptibility
Female
Fibroblasts - cytology
Gene loci
Genetic aspects
Genetic Predisposition to Disease
Genetics and Genomics/Animal Genetics
Genetics and Genomics/Genetics of Disease
Immunology/Innate Immunity
Infectious Diseases/Bacterial Infections
Kinases
Macrophages - immunology
Macrophages - microbiology
Mice
Microbiology/Cellular Microbiology and Pathogenesis
Microbiology/Innate Immunity
Molecular Sequence Data
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - immunology
Physiological aspects
Protein Structure, Tertiary
Proteins
Rats
Rats, Inbred BN
Rats, Inbred Dahl
Rats, Inbred F344
Rats, Inbred SHR
Rats, Inbred WKY
Rats, Sprague-Dawley
Rodents
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Description
Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1000906