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On the role of macrophages in anthrax
P C Hanna1, D Acosta, R J Collier
1Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115.
Abstract:
Bacillus anthracis, the causative agent of anthrax, produces systemic shock and death in susceptible animals, primarily through the action of its lethal toxin. This toxin, at high concentrations, induces lysis of macrophages in vitro but shows little or no effect on other cells. We found that when mice were specifically depleted of macrophages by silica injections, they became resistant to the toxin. Sensitivity could be restored by coinjection of toxin-sensitive cultured macrophages (RAW 264.7 cells) but not by coinjection of other cell lines tested. These results implied that macrophages mediate the action of lethal toxin in vivo and led us to investigate their role in death of the mammalian host. Sublytic concentrations of lethal toxin, orders of magnitude lower than those required to induce lysis of RAW 264.7 cells, were found to induce these cells to express interleukin 1 (IL-1) and tumor necrosis factor in vitro. Passive immunization against IL-1 or injection of an IL-1 receptor antagonist protected mice from toxin challenge, whereas anti-tumor necrosis factor provided little, if any, protection. These results imply that systemic shock and death from anthrax result primarily from the effects of high levels of cytokines, principally IL-1, produced by macrophages that have been stimulated by the anthrax lethal toxin.
Insights
Anthrax lethal toxin primarily kills by stimulating macrophages to release interleukin-1 (IL-1). Blocking IL-1 protects mice, revealing a key mechanism in anthrax pathogenesis.
Area of Science:
- Immunology
- Pathogenesis
- Microbiology
Background:
- Bacillus anthracis lethal toxin causes severe disease and death.
- The toxin's precise mechanism in vivo, particularly its cellular targets, remains incompletely understood.
Purpose of the Study:
- To elucidate the role of macrophages in Bacillus anthracis lethal toxin-induced pathogenesis.
- To identify the specific host immune mediators involved in toxin-induced shock and death.
Main Methods:
- Mice were depleted of macrophages using silica injections to assess toxin resistance.
- Cultured macrophages (RAW 264.7) and other cell lines were used to investigate cellular responses to the toxin.
- Cytokine expression (IL-1, TNF) was measured in toxin-stimulated macrophages.
- Mice were treated with antibodies against IL-1 or TNF, or an IL-1 receptor antagonist, and challenged with lethal toxin.
Main Results:
- Macrophage depletion conferred resistance to anthrax lethal toxin in mice.
- Toxin-stimulated macrophages released significant levels of interleukin-1 (IL-1) and tumor necrosis factor (TNF).
- Passive immunization against IL-1 or IL-1 receptor antagonism significantly protected mice from lethal toxin challenge, while anti-TNF had minimal effect.
Conclusions:
- Macrophages are critical mediators of Bacillus anthracis lethal toxin's effects in vivo.
- Anthrax lethal toxin induces systemic shock and death primarily through macrophage-derived cytokines, with IL-1 playing a principal role.