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Infection and Immunity, August 2004, p. 4439-4447, Vol. 72, No. 8
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.8.4439-4447.2004

Mouse Susceptibility to Anthrax Lethal Toxin Is Influenced by Genetic Factors in Addition to Those Controlling Macrophage Sensitivity

Mahtab Moayeri,1 Nathaniel W. Martinez,1 Jason Wiggins,1 Howard A. Young,2 and Stephen H. Leppla1*

Microbial Pathogenesis Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892,1 Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 217022

Received 19 February 2004/ Returned for modification 30 March 2004/ Accepted 19 April 2004

Bacillus anthracis lethal toxin (LT) produces symptoms of anthrax in mice and induces rapid lysis of macrophages (M{phi}) derived from certain inbred strains. We used nine inbred strains and two inducible nitric oxide synthase (iNOS) knockout C57BL/6J strains polymorphic for the LT M{phi} sensitivity Kif1C locus to analyze the role of M{phi} sensitivity (to lysis) in LT-mediated cytokine responses and lethality. LT-mediated induction of cytokines KC, MCP-1/JE, MIP-2, eotaxin, and interleukin-1ß occurred only in mice having LT-sensitive M{phi}. However, while iNOS knockout C57BL/6J mice having LT-sensitive M{phi} were much more susceptible to LT than the knockout mice with LT-resistant M{phi}, a comparison of susceptibilities to LT in the larger set of inbred mouse strains showed a lack of correlation between M{phi} sensitivity and animal susceptibility to toxin. For example, C3H/HeJ mice, harboring LT-sensitive M{phi} and having the associated LT-mediated cytokine response, were more resistant than mice with LT-resistant M{phi} and no cytokine burst. Toll-like receptor 4 (Tlr4)-deficient, lipopolysaccharide-nonresponsive mice were not more resistant to LT. We also found that CAST/Ei mice are uniquely sensitive to LT and may provide an economical bioassay for toxin-directed therapeutics. The data indicate that while the cytokine response to LT in mice requires M{phi} lysis and while M{phi} sensitivity in the C57BL/6J background is sufficient for BALB/cJ-like mortality of that strain, the contribution of M{phi} sensitivity and cytokine response to animal susceptibility to LT differs among other inbred strains. Thus, LT-mediated lethality in mice is influenced by genetic factors in addition to those controlling M{phi} lysis and cytokine response and is independent of Tlr4 function.

* Corresponding author. Mailing address: Building 30, Room 303, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 594-2865. Fax: (301) 480-0326. E-mail: sleppla{at}niaid.nih.gov.

Editor: J. D. Clements

Infection and Immunity, August 2004, p. 4439-4447, Vol. 72, No. 8
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.8.4439-4447.2004




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