Susceptibility to Anthrax Lethal Toxin-induced Rat Death is Controlled by a Single Chromosome 10 Locus That Includes RNlrp1

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2010 May 27

PMID 20502689

Citations 55

Authors

Zachary L Newman

Morton P Printz

Shihui Liu

Devorah Crown

Laura Breen

Sharmina Miller-Randolph

Pamela Flodman

Stephen H Leppla

Mahtab Moayeri

Affiliations

Soon will be listed here.

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.

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References

Feldmeyer L, Keller M, Niklaus G, Hohl D, Werner S, Beer H . The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes. Curr Biol. 2007; 17(13):1140-5. DOI: 10.1016/j.cub.2007.05.074. View

Jirout M, Krenova D, Kren V, Breen L, Pravenec M, Schork N . A new framework marker-based linkage map and SDPs for the rat HXB/BXH strain set. Mamm Genome. 2003; 14(8):537-46. DOI: 10.1007/s00335-003-2266-z. View

Wickliffe K, Leppla S, Moayeri M . Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell Microbiol. 2007; 10(2):332-43. PMC: 2515708. DOI: 10.1111/j.1462-5822.2007.01044.x. View

Gupta P, Moayeri M, Crown D, Fattah R, Leppla S . Role of N-terminal amino acids in the potency of anthrax lethal factor. PLoS One. 2008; 3(9):e3130. PMC: 2518864. DOI: 10.1371/journal.pone.0003130. View

Nour A, Yeung Y, Santambrogio L, Boyden E, Stanley E, Brojatsch J . Anthrax lethal toxin triggers the formation of a membrane-associated inflammasome complex in murine macrophages. Infect Immun. 2009; 77(3):1262-71. PMC: 2643637. DOI: 10.1128/IAI.01032-08. View

Moayeri M, Webster J, Wiggins J, Leppla S, Sternberg E . Endocrine perturbation increases susceptibility of mice to anthrax lethal toxin. Infect Immun. 2005; 73(7):4238-44. PMC: 1168625. DOI: 10.1128/IAI.73.7.4238-4244.2005. View

Liao K, Mogridge J . Expression of Nlrp1b inflammasome components in human fibroblasts confers susceptibility to anthrax lethal toxin. Infect Immun. 2009; 77(10):4455-62. PMC: 2747971. DOI: 10.1128/IAI.00276-09. View

BEALL F, DALLDORF F . The pathogenesis of the lethal effect of anthrax toxin in the rat. J Infect Dis. 1966; 116(3):377-89. DOI: 10.1093/infdis/116.3.377. View

Nye S, Wittenburg A, Evans D, OConnor J, Roman R, Jacob H . Rat survival to anthrax lethal toxin is likely controlled by a single gene. Pharmacogenomics J. 2007; 8(1):16-22. DOI: 10.1038/sj.tpj.6500448. View

10.

Magitta N, Boe Wolff A, Johansson S, Skinningsrud B, Lie B, Myhr K . A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes. Genes Immun. 2008; 10(2):120-4. DOI: 10.1038/gene.2008.85. View

11.

Fink S, Bergsbaken T, Cookson B . Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc Natl Acad Sci U S A. 2008; 105(11):4312-7. PMC: 2393760. DOI: 10.1073/pnas.0707370105. View

12.

Muehlbauer S, Evering T, Bonuccelli G, Squires R, Ashton A, Porcelli S . Anthrax lethal toxin kills macrophages in a strain-specific manner by apoptosis or caspase-1-mediated necrosis. Cell Cycle. 2007; 6(6):758-66. DOI: 10.4161/cc.6.6.3991. View

13.

Watters J, Dewar K, Lehoczky J, Boyartchuk V, Dietrich W . Kif1C, a kinesin-like motor protein, mediates mouse macrophage resistance to anthrax lethal factor. Curr Biol. 2001; 11(19):1503-11. DOI: 10.1016/s0960-9822(01)00476-6. View

14.

Printz M, Jirout M, Jaworski R, Alemayehu A, Kren V . Genetic Models in Applied Physiology. HXB/BXH rat recombinant inbred strain platform: a newly enhanced tool for cardiovascular, behavioral, and developmental genetics and genomics. J Appl Physiol (1985). 2003; 94(6):2510-22. DOI: 10.1152/japplphysiol.00064.2003. View

15.

de Rivero Vaccari J, Lotocki G, Alonso O, Bramlett H, Dietrich W, Keane R . Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J Cereb Blood Flow Metab. 2009; 29(7):1251-61. PMC: 2846547. DOI: 10.1038/jcbfm.2009.46. View

16.

Park S, Leppla S . Optimized production and purification of Bacillus anthracis lethal factor. Protein Expr Purif. 2000; 18(3):293-302. DOI: 10.1006/prep.2000.1208. View

17.

Martinon F, Mayor A, Tschopp J . The inflammasomes: guardians of the body. Annu Rev Immunol. 2009; 27:229-65. DOI: 10.1146/annurev.immunol.021908.132715. View

18.

Moayeri M, Crown D, Dorward D, Gardner D, Ward J, Li Y . The heart is an early target of anthrax lethal toxin in mice: a protective role for neuronal nitric oxide synthase (nNOS). PLoS Pathog. 2009; 5(5):e1000456. PMC: 2680977. DOI: 10.1371/journal.ppat.1000456. View

19.

Arora N, Klimpel K, Singh Y, Leppla S . Fusions of anthrax toxin lethal factor to the ADP-ribosylation domain of Pseudomonas exotoxin A are potent cytotoxins which are translocated to the cytosol of mammalian cells. J Biol Chem. 1992; 267(22):15542-8. View

20.

Ezzell J, Ivins B, Leppla S . Immunoelectrophoretic analysis, toxicity, and kinetics of in vitro production of the protective antigen and lethal factor components of Bacillus anthracis toxin. Infect Immun. 1984; 45(3):761-7. PMC: 263363. DOI: 10.1128/iai.45.3.761-767.1984. View