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

J Clin Invest. 2003 Sep;112(5):670-82. doi: 10.1172/JCI17991.

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 C57BL/6J mice. BALB/cJ mice became terminally ill earlier and with higher frequency than C57BL/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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anthrax / etiology
  • Antigens, Bacterial*
  • Bacterial Toxins / toxicity*
  • Bone Marrow / pathology
  • Cytokines / biosynthesis
  • Endothelial Growth Factors / biosynthesis
  • Fas Ligand Protein
  • Hypoxia / chemically induced*
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Liver / pathology
  • Lymphokines / biosynthesis
  • Macrophages / metabolism
  • Male
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Spleen / pathology
  • Thymus Gland / pathology
  • Tumor Necrosis Factor-alpha / physiology*
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Antigens, Bacterial
  • Bacterial Toxins
  • Cytokines
  • Endothelial Growth Factors
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Membrane Glycoproteins
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • anthrax toxin