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.
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
Mahtab
M
Moayeri
Jeanette I
JI
Webster
Jason F
JF
Wiggins
Stephen H
SH
Leppla
Esther M
EM
Sternberg
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