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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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 2

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LT effects on circulating monocytes, neutrophils, and platelets. Graphs ...
LT effects on circulating monocytes, neutrophils, and platelets. Graphs show circulating monocyte (a), neutrophil (b), and platelet (c) levels in response to LT treatment as a percentage of untreated controls. Values are the mean of the percentage change in two to eight individual pooled experiments using both i.p. and i.v. treated mice at doses of 50 μg, 100 μg, and 250 μg LT, based on groups of two to four mice per time point. Values were calculated as the percentage change in cell number relative to a PBS-treated control group (two to four mice per experiment). Absolute control cell numbers differed in each experiment. Error bars indicate SD for the mean percentage change. Unpaired t test analysis indicates that differences in curves in a are statistically significant at 18, 24, and 36 hours (P = 0.008, P < 0.0001, and P < 0.0001, respectively). In b, differences in the two strains are only significant at 10 and 12 hours (P = 0.002 and P = 0.004, respectively). In c, differences in the two strains are not significant at any point. In a, differences relative to 0 hours are statistically significant at all times past 6 hours in BALB/cJ and at 6, 10, 12, and 36 hours in C57BL/6J. In b and c, differences relative to 0 hours are statistically significant beyond 10 hours in BALB/cJ and beyond 24 hours in C57BL/6J.