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Toxin-Deficient Mutants of Bacillus anthracis Are Lethal in a Murine Model for Pulmonary Anthrax

Sara Heninger,^1, Melissa Drysdale,^2, Julie Lovchik,² Julie Hutt,³ Mary F. Lipscomb,⁴ Theresa M. Koehler,⁵ and C. Rick Lyons^1,2*

Department of Molecular Genetics and Microbiology, University of New Mexico Health Science Center, Albuquerque, New Mexico 87131,¹ Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico 87131,² Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87131,³ Department of Pathology, University of New Mexico Health Science Center, Albuquerque, New Mexico 87131,⁴ Department of Microbiology and Molecular Genetics, The University of Texas Houston Health Science Center, Houston, Texas 77030⁵

Received 4 May 2006/ Returned for modification 14 June 2006/ Accepted 8 August 2006

Bacillus anthracis, the etiologic agent of anthrax, produces at least three primary virulence factors: lethal toxin, edema toxin, and a capsule. The capsule is absolutely required for dissemination and lethality in a murine model of inhalation anthrax, yet the roles for the toxins during infection are ill-defined. We show in a murine model that when spores of specific toxin-null mutants are introduced into the lung, dissemination and lethality are comparable to those of the parent strain. Mutants lacking one or more of the structural genes for the toxin proteins, i.e., protective antigen, lethal factor, and edema factor, disseminated from the lung to the spleen at rates similar to that of the virulent parental strain. The 50% lethal dose (LD₅₀) and mean time to death (MTD) of the mutants did not differ significantly from those of the parent. The LD₅₀s or MTDs were also unaffected relative to those of the parent strain when mice were inoculated intravenously with vegetative cells. Nonetheless, histopathological examination of tissues revealed subtle but distinct differences in infections by the parent compared to some toxin mutants, suggesting that the host response is affected by toxin proteins synthesized during infection.

Published ahead of print on 21 August 2006.

Editor: J. T. Barbieri

These authors contributed equally to this work.

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