Abstract
Anthrax lethal toxin (LT) is a major virulence factor of Bacillus anthracis. LT challenge suppresses platelet counts and platelet function in mice, however, the mechanism responsible for thrombocytopenia remains unclear. LT inhibits cellular mitogen-activated protein kinases (MAPKs), which are vital pathways responsible for cell survival, differentiation, and maturation. One of the MAPKs, the MEK1/2-extracellular signal-regulated kinase pathway, is particularly important in megakaryopoiesis. This study evaluates the hypothesis that LT may suppress the progenitor cells of platelets, thereby inducing thrombocytopenic responses. Using cord blood-derived CD34+ cells and mouse bone marrow mononuclear cells to perform in vitro differentiation, this work shows that LT suppresses megakaryopoiesis by reducing the survival of megakaryocytes. Thrombopoietin treatments can reduce thrombocytopenia, megakaryocytic suppression, and the quick onset of lethality in LT-challenged mice. These results suggest that megakaryocytic suppression is one of the mechanisms by which LT induces thrombocytopenia. These findings may provide new insights for developing feasible approaches against anthrax.
Highlights
Bacillus anthracis, the etiological agent of anthrax, is a Grampositive, nonmotile, aerobic, spore-forming, rod-shaped bacterium [1]
The DNA contents of R2 cells are similar to platelets (Figure 3B vs. Figure 4B, b-3; sub-G1), flow cytometry data revealed that lethal toxin (LT)-challenged R2 cells did not fully match the size and granularity properties of mature platelets isolated from cord blood (Figure 4A, R2 vs Figure 4B, b-1 showed as a linear scale, b2 showed as logarithmic scale)
Evidence from this study suggests that the megakaryocyte is one of the target cells of LT, and the suppression of megakaryopoiesis is one of the mechanisms of LT induced thrombocytopenia
Summary
The etiological agent of anthrax, is a Grampositive, nonmotile, aerobic, spore-forming, rod-shaped bacterium [1]. Anthrax lethal toxin (LT) is a major virulence factor of B. anthracis, and it consists of two polypeptides: protective antigen (PA, 83 kDa) and lethal factor (LF, 90 kDa) [2]. LF is a zincdependent metalloprotease that cleaves the N-terminal domain of all the mitogen-activated protein kinase (MAPK) kinases (MKKs/ MEKs) from MEK1 to MEK7, except MEK5 [3]. LF is toxic only when combined with PA, a cellular receptorbinding component that delivers LF into cells [2], forming a lethal toxin (LT). PA binds to two known cell-surface receptors: tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2) [6,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
