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Bacillus anthracis lethal toxin induces TNF-alpha-independent hypoxia-mediated toxicity in mice

  1. Author:
    Moayeri, M.
    Haines, D.
    Young, H. A.
    Leppla, S. H.

  2. Author Address

    NIAID, NIH, Bldg 30,Room 303, Bethesda, MD 20892 USA NIAID, NIH, Bethesda, MD 20892 USA NCI, Vet Pathol Sect, Pathol & Histotechnol Lab, Sci Applicat Int Corp, Frederick, MD 21701 USA NCI, Ctr Canc Res, Expt Immunol Lab, Frederick, MD 21701 USA Leppla SH NIAID, NIH, Bldg 30,Room 303, Bethesda, MD 20892 USA
    1. Year: 2003
  2. Journal: Journal of Clinical Investigation
    1. 112
    2. 5
    3. Pages: 670-682
  4. Type of Article: Article
  1. Abstract:

    Bacillus anthracis lethal toxin (LT) is the major virulence factor of anthrax and reproduces most of the laboratory manifestations of the disease in animals. We studied LT toxicity in BALB/cJ and CS7BL/6J mice. BALB/cJ mice became terminally ill earlier and with higher frequency than CS7BL/6J mice. Timed histopathological analysis identified bone marrow, spleen, and liver as major affected organs in both mouse strains. LT induced extensive hypoxia. Crisis was due to extensive liver necrosis accompanied by pleural edema. There was no evidence of disseminated intravascular coagulation or renal dysfunction. Instead, analyses revealed hepatic dysfunction, hypoalbuminemia, and vascular/oxygenation insufficiency. Of 50 cytokines analyzed, BALB/cJ mice showed rapid but transitory increases in specific factors including KC, MCP-1/JE, IL-6, MIP-2, G-CSF, GM-CSF, eotaxin, FasL, and IL-1beta. No changes in TNF-alpha occurred. The C57BL/6J mice did not mount a similar cytokine response. These factors were not induced in vitro by LT treatment of toxin-sensitive macrophages. The evidence presented shows that LT kills mice through a TNF-alpha-independent, FasL-independent, noninflammatory mechanism that involves hypoxic tissue injury but does not require macrophage sensitivity to toxin.

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