Endocrine perturbation increases susceptibility of mice to anthrax lethal toxin.
Bacillus anthracis lethal toxin (LT) causes vascular collapse and high lethality in BALB/cJ mice, intermediate lethality in C57BL/6J mice, and no lethality in DBA/2J mice. We found that adrenalectomized (ADX) mice of all three strains had increased susceptibility to LT. The increased susceptibility of ADX-DBA/2J mice was not accompanied by changes in their macrophage sensitivity or cytokine response to LT. DBA/2J mice showed no change in serum corticosteroid levels in response to LT injection, while BALB/cJ mice showed a fivefold increase in serum corticosterone. However, LT inhibited dexamethasone (DEX)-induced glucocorticoid receptor gene activation to similar extents in all three strains. DEX treatment did not rescue ADX mice from LT-mediated mortality. Surprisingly, oral DEX treatment also sensitized adrenally intact DBA/2J mice to LT lethality at all doses tested and also exacerbated LT-mediated pathogenesis and mortality in BALB/cJ mice. Aldosterone did not protect ADX mice from toxin challenge. These results indicate that susceptibility to anthrax LT in mice depends on a fine but easily perturbed balance of endocrine functions. Thus, the potentially detrimental consequences of steroid therapy for anthrax must be considered in treatment protocols for this disease.
Moayeri
Mahtab
M
Mcrobial Pathogenesis Section, National Institute of Allergy and Infectious Diseases, Building 30, Room 303, National Institutes of Health, Bethesda, Maryland 20892, USA. mmoayeri@niaid.nih.gov
Webster
Jeanette I
JI
Wiggins
Jason F
JF
Leppla
Stephen H
SH
Sternberg
Esther M
EM
D000315:Adrenalectomy; D000450:Aldosterone / Q000627:therapeutic use; D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010913:Pituitary-Adrenal System / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000502:physiology
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D016207:Cytokines; D011965:Receptors, Glucocorticoid; C030325:anthrax toxin; D000450:Aldosterone; D003907:Dexamethasone; D003345:Corticosterone