title: Erythropoiesis suppression is associated with anthrax lethal toxin-mediated pathogenic progression.
abstract: Anthrax is a disease caused by the bacterium Bacillus anthracis, which results in high mortality in animals and humans. Although some of the mechanisms are already known such as asphyxia, extensive knowledge of molecular pathogenesis of this disease is deficient and remains to be further investigated. Lethal toxin (LT) is a major virulence factor of B. anthracis and a specific inhibitor/protease of mitogen-activated protein kinase kinases (MAPKKs). Anthrax LT causes lethality and induces certain anthrax-like symptoms, such as anemia and hypoxia, in experimental mice. Mitogen-activated protein kinases (MAPKs) are the downstream pathways of MAPKKs, and are important for erythropoiesis. This prompted us to hypothesize that anemia and hypoxia may in part be exacerbated by erythropoietic dysfunction. As revealed by colony-forming cell assays in this study, LT challenges significantly reduced mouse erythroid progenitor cells. In addition, in a proteolytic activity-dependent manner, LT suppressed cell survival and differentiation of cord blood CD34(+)-derived erythroblasts in vitro. Suppression of cell numbers and the percentage of erythroblasts in the bone marrow were detected in LT-challenged C57BL/6J mice. In contrast, erythropoiesis was provoked through treatments of erythropoietin, significantly ameliorating the anemia and reducing the mortality of LT-treated mice. These data suggested that suppressed erythropoiesis is part of the pathophysiology of LT-mediated intoxication. Because specific treatments to overcome LT-mediated pathogenesis are still lacking, these efforts may help the development of effective treatments against anthrax.
authors: Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan ; Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan.
authors: Hsin-Hou
authors: HH
authors: Chang
authors: Tsung-Pao
authors: TP
authors: Wang
authors: Po-Kong
authors: PK
authors: Chen
authors: Yo-Yin
authors: YY
authors: Lin
authors: Chih-Hsien
authors: CH
authors: Liao
authors: Ting-Kai
authors: TK
authors: Lin
authors: Ya-Wen
authors: YW
authors: Chiang
authors: Wen-Bin
authors: WB
authors: Lin
authors: Chih-Yu
authors: CY
authors: Chiang
authors: Jyh-Hwa
authors: JH
authors: Kau
authors: Hsin-Hsien
authors: HH
authors: Huang
authors: Hui-Ling
authors: HL
authors: Hsu
authors: Chi-Yuan
authors: CY
authors: Liao
authors: Der-Shan
authors: DS
authors: Sun
mesh_terms: D000740:Anemia / Q000150:complications / Q000473:pathology; D000818:Animals; D000881:Anthrax / Q000150:complications / Q000382:microbiology* / Q000473:pathology*; D000942:Antigens, Bacterial / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001427:Bacterial Toxins / Q000633:toxicity*; D055162:Biocatalysis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D018450:Disease Progression; D041905:Erythroid Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D059748:Proteolysis / Q000187:drug effects; D016019:Survival Analysis
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D004921:Erythropoietin
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