Date of Award


Degree Type


Degree Name

Master of Science


Microbiology and Immunology


Lethal toxin (LeTx) is a critical virulence factor of B. anthracis causing immune suppression and toxic shock of the infected host. It inhibits cytokine production and cell proliferation/differentiation in various immune cells. In the present study, I demonstrated that a brief exposure to LeTx caused a continual MEKl cleavage and prevented TNF-α production in non-proliferating cells such as human peripheral blood mononuclear cells or mouse primary peritoneal macrophages. In human monocytic cell lines U-937 and THP-1, LeTx induced cell cycle arrest in G0-Gι phase by rapid down-regulation of cyclin D1∕D2 and checkpoint kinase 1 through MEKl inhibition. However, THP-1 cells adaptively adjusted to LeTx and overrode cell cycle arrest by activating the PI3K∕Akt signaling pathway. Activated Akt inhibited GSK3 and prevented proteasome-mediated cyclin D1 degradation in LeTx-intoxicated THP-1 cells. Recovery from cell cycle arrest was required before recovering from on-going MEKl cleavage and suppression of TNF-α production. This study demonstrated that modulation of PI3K∕Akt∕GSK3 signaling cascades can be beneficial for protecting or facilitating recovery from cellular LeTx intoxication in cells that depend on basal MEKl activity for proliferation.



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