Inhibition of mitogen-activated protein kinase signalling by Bacillus anthracis lethal toxin causes destabilization of interleukin-8 mRNA

Abstract

Bacillus anthracis must overcome host innate immune defences to establish a systemic anthrax infection. This is facilitated in part by lethal toxin (LT), a secreted virulence factor that consists of a cell-binding moiety, protective antigen (PA), and an enzymatic moiety, lethal factor (LF). PA binds cells through protein receptors and mediates the delivery of LF to the cytosol. LF is a protease that cleaves amino-terminal fragments from mitogen-activated protein kinase kinases (MAPKKs), preventing phosphorylation of their downstream targets. Here we report that LT reduces the amount of interleukin (IL)-8 produced and secreted by human endothelial cells. The reduction of IL-8 levels by LT was not attributable to reduced expression from the IL-8 promoter, but resulted from destabilization of IL-8 mRNA. Destabilization by LT was mediated through the 3' untranslated region of the IL-8 transcript and could be mimicked by pharmacological inhibitors of MAPK pathways. LT diminished the induction of IL-8 mRNA and protein by lipopolysaccharide, indicating that the toxin can impair the ability of these cells to initiate an immune response. Destabilization of a cytokine transcript represents a new interference strategy used by either a bacterial or viral pathogen to reduce cytokine expression and may help B. anthracis to evade host immune defences.