Bacillus anthracis lethal toxin induces TNF-α–independent hypoxia-mediated toxicity in mice
Mahtab Moayeri, … , Howard A. Young, Stephen H. Leppla
Mahtab Moayeri, … , Howard A. Young, Stephen H. Leppla
Published September 1, 2003
Citation Information: J Clin Invest. 2003;112(5):670-682. https://doi.org/10.1172/JCI17991.
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Article Infectious disease

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

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-1β. No changes in TNF-α 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-α–independent, FasL-independent, noninflammatory mechanism that involves hypoxic tissue injury but does not require macrophage sensitivity to toxin.

Authors

Mahtab Moayeri, Diana Haines, Howard A. Young, Stephen H. Leppla

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Figure 1

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LT toxicity in inbred mice. (a and b) Comparison of four doses of PA plu...
LT toxicity in inbred mice. (a and b) Comparison of four doses of PA plus LF in BALB/cJ (a) and C57BL/6J (b) mice. Mice were injected i.p. with 1 ml of toxin in PBS. Results are based on n = 12, n = 24, n = 60, and n = 12 for 10 μg, 50 μg, 100 μg, and 250 μg of each toxin component. (c) Comparison of i.p. and i.v. routes of injection in the BALB/cJ mouse. Results are based on n = 18, n = 24, n = 60, and n = 20 for 50 μg i.v., 50 μg i.p., 100 μg i.p., and 100 μg i.v. of each toxin component. The differences in i.p. and i.v. survival curves at both 50 and 100 μg are not statistically significant by the log-rank test (P = 0.0807 and 0.553, respectively). The difference between the 50-μg i.p. curve and both 100-μg curves is statistically significant (P = 0.0013 and P = 0.0002). (d) Data from a and b for the 100-μg dose injected i.p., presented to allow direct comparison of the single selected dose used in all further experiments.