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PMID: 12952916 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Bacillus anthracis lethal toxin induces TNF-alpha-independent hypoxia-mediated toxicity in mice.

The Journal of clinical investigation ·Vol. 112 ·No. 5 ·2003-09-00 ·Pages 670-82

Moayeri M, Haines D, Young HA, Leppla SH

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

MeSH Terms
Animals Anthrax/etiology Antigens, Bacterial Bacterial Toxins/toxicity Bone Marrow/pathology Cytokines/biosynthesis Endothelial Growth Factors/biosynthesis Fas Ligand Protein Hypoxia/chemically induced Intercellular Signaling Peptides and Proteins/biosynthesis Liver/pathology Lymphokines/biosynthesis Macrophages/metabolism Male Membrane Glycoproteins/physiology Mice Mice, Inbred BALB C Mice, Inbred C57BL Spleen/pathology Thymus Gland/pathology Tumor Necrosis Factor-alpha/physiology Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors
Chemicals
Antigens, Bacterial Bacterial Toxins Cytokines Endothelial Growth Factors Fas Ligand Protein Fasl protein, mouse Intercellular Signaling Peptides and Proteins Lymphokines Membrane Glycoproteins Tumor Necrosis Factor-alpha Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors anthrax toxin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Moayeri Mahtab
National Institutes of Health, NIH, Bethesda, Maryland 20892, USA.
Haines Diana
Young Howard A
Leppla Stephen H
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI17991
Published
2003-09-00
Pages
670-82
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC182199
Subset
IM
Grants
NCI NIH HHS · N01CO12400 · United States
PHS HHS · N01-C0-12400 · United States
Corrections
CommentIn
PMID: 12952914
External Links
PubMed source DOI: 10.1172/JCI17991 PMC Full Text View journal details
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