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Allelic Variation on Murine Chromosome 11 Modifies Host Inflammatory Responses and Resistance to Bacillus anthracis

By Jill K. Terra, Bryan France, Christopher K. Cote, Amy Jenkins, Joel A. Bozue, Susan L. Welkos, Ragini Bhargava, Chi-Lee Ho, Margarete Mehrabian, Calvin Pan, Aldons J. Lusis, Richard C. Davis, Steven M. LeVine and Kenneth A. Bradley


Anthrax is a potentially fatal disease resulting from infection with Bacillus anthracis. The outcome of infection is influenced by pathogen-encoded virulence factors such as lethal toxin (LT), as well as by genetic variation within the host. To identify host genes controlling susceptibility to anthrax, a library of congenic mice consisting of strains with homozygous chromosomal segments from the LT-responsive CAST/Ei strain introgressed on a LT-resistant C57BL/6 (B6) background was screened for response to LT. Three congenic strains containing CAST/Ei regions of chromosome 11 were identified that displayed a rapid inflammatory response to LT similar to, but more severe than that driven by a LT-responsive allele of the inflammasome constituent NRLP1B. Importantly, increased response to LT in congenic mice correlated with greater resistance to infection by the Sterne strain of B. anthracis. The genomic region controlling the inflammatory response to LT was mapped to 66.36–74.67 Mb on chromosome 11, a region that encodes the LT-responsive CAST/Ei allele of Nlrp1b. However, known downstream effects of NLRP1B activation, including macrophage pyroptosis, cytokine release, and leukocyte infiltration could not fully explain the response to LT or the resistance to B. anthracis Sterne in congenic mice. Further, the exacerbated response in congenic mice is inherited in a recessive manner while the Nlrp1b-mediated response to LT is dominant. Finally, congenic mice displayed increased responsiveness in a model of sepsis compared with B6 mice. In total, these data suggest that allelic variation of one or more chromosome 11 genes in addition to Nlrp1b controls the severity of host response to multiple inflammatory stimuli and contributes to resistance to B. anthracis Sterne. Expression quantitative trait locus analysis revealed 25 genes within this region as high priority candidates for contributing to the host response to LT

Topics: Research Article
Publisher: Public Library of Science
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Provided by: PubMed Central

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  22. (2010). Cutting edge: resistance to Bacillus anthracis infection mediated by a lethal toxin sensitive allele of Nalp1b/Nlrp1b.
  23. (1986). Differences in susceptibility of inbred mice to Bacillus anthracis.
  24. (2010). Dual roles of endogenous platelet-activating factor acetylhydrolase in a murine model of necrotizing enterocolitis.
  25. (2008). Early interactions between fully virulent Bacillus anthracis and macrophages that influence the balance between spore clearance and development of a lethal infection.
  26. (2002). Effect of Bacillus anthracis lethal toxin on human peripheral blood mononuclear cells.
  27. (2003). Gene expression profiles of nondiabetic and diabetic obese mice suggest a role of hepatic lipogenic capacity in diabetes susceptibility.
  28. (2001). Genetic, physical, and transcript map of the Ltxs1 region of mouse chromosome 11.
  29. (2001). Genetical genomics: the added value from segregation.
  30. (2003). Genetics of gene expression surveyed in maize, mouse and man.
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  32. (2009). Innate immune responses to danger signals in systemic inflammatory response syndrome and sepsis.
  33. (2005). Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease.
  34. (2004). Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats.
  35. (1998). Ltx1, a mouse locus that influences the susceptibility of macrophages to cytolysis caused by intoxication with Bacillus anthracis lethal factor, maps to chromosome 11.
  36. (2002). Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition.
  37. (2005). Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation.
  38. (2001). Macrophage-derived cell lines do not express proinflammatory cytokines after exposure to Bacillus anthracis lethal toxin.
  39. (2009). MAPK cascade signalling networks in plant defence.
  40. (1998). Mapping of genetic modulators of natural resistance to infection with Salmonella typhimurium in wild-derived mice.
  41. (2008). Mapping the genetic architecture of gene expression in human liver.
  42. (2003). Mechanisms of immune resolution.
  43. (2006). Molecular genetic analysis of the Idd4 locus implicates the IFN response in type 1 diabetes susceptibility in nonobese diabetic mice.
  44. (2007). Molecular genetic analysis of two loci
  45. (2004). Mouse susceptibility to anthrax lethal toxin is influenced by genetic factors in addition to those controlling macrophage sensitivity.
  46. (2011). Muramyldipeptide augments the actions of lipopolysaccharide in mice by stimulating macrophages to produce pro-IL-1{beta} and by down-regulation of the suppressor of cytokine signaling 1 (SOCS1).
  47. (2005). Murine macrophage transcriptional responses to Bacillus anthracis infection and intoxication.
  48. (2005). MyD88-dependent signaling contributes to protection following Bacillus anthracis spore challenge of mice: implications for Toll-like receptor signaling.
  49. (2011). MyD88-dependent signaling protects against anthrax lethal toxin-induced impairment of intestinal barrier function.
  50. (2006). Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin.
  51. (2010). negatively regulates sepsis-induced inflammation.
  52. (2010). Netrin-1 regulates Th1/Th2/ Th17 cytokine production and inflammation through UNC5B receptor and protects kidney against ischemia-reperfusion injury.
  53. (2006). New insights into the functions of anthrax toxin.
  54. (1993). Non-toxigenic derivatives of the Ames strain of Bacillus anthracis are fully virulent for mice: role of plasmid pX02 and chromosome in strain-dependent virulence.
  55. (2000). Optimized production and purification of Bacillus anthracis lethal factor.
  56. (1988). Pathogenesis and genetic control of resistance to the Sterne strain of Bacillus anthracis.
  57. (1989). Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2.
  58. (2005). Pro- and anti-inflammatory effects of IL-4: from studies in mice to therapy of autoimmune diseases in humans. Ernst Schering Res Found Workshop.
  59. (2007). Rat survival to anthrax lethal toxin is likely controlled by a single gene.
  60. (2010). Regulation of lipopolysaccharide-induced inflammatory response and endotoxemia by beta-arrestins.
  61. (1989). Resistance to the Sterne strain of B. anthracis: phagocytic cell responses of resistant and susceptible mice.
  62. (2008). Role of Nterminal amino acids in the potency of anthrax lethal factor.
  63. (2011). SR-PSOX/ CXCL16 plays a critical role in the progression of colonic inflammation.
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  65. (2006). Sublethal doses of Bacillus anthracis lethal toxin inhibit inflammation with lipopolysaccharide and Escherichia coli challenge but have opposite effects on survival.
  66. (2003). Susceptibility to anthrax lethal toxin is controlled by three linked quantitative trait Loci.
  67. (2009). Targeting of immune signalling networks by bacterial pathogens.
  68. (2009). The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis.
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  70. (2002). TNF receptor 1, IL-1 receptor, and iNOS genetic knockout mice are not protected from anthrax infection.
  71. (2010). Update on biology: uric acid and the activation of immune and inflammatory cells.
  72. (1967). Value of field data for extrapolation in anthrax.

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