Novel Functions of Anthrax Lethal Toxin




Tan, Yian Kim

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Bacillus anthracis is a gram positive spore-forming bacterium that can cause cutaneous, gastrointestinal or inhalational anthrax in many animals and humans. Vegetative B. anthracis generates two essential virulence factors: the anthrax lethal toxin and the poly-γ-D glutamic acid capsule. The primary virulence factor is a secreted zinc-dependent metalloprotease toxin known as lethal factor (LF), which is introduced into the cytosol by protective antigen (PA) through its receptors on the cells. LF exerts its toxic effect through the disruption of mitogen-activated protein kinase kinase (MAPKK) signaling pathway, which is essential in mounting an efficient and prompt immune response against the invading pathogen. LF also mediates the destruction of host cells through either necrotic cell death or apoptosis pathway depending upon the genetic background of the cell types. Autophagy is an evolutionary conserved intracellular process whereby cells break down long-lived proteins and organelles. Accumulating evidences suggest increasing physiological significance of autophagy in pathogenesis of infectious diseases. In addition to the myriad of effects that LT exerts on different cell types, we describe herein a novel effect of LT-induced autophagy on mammalian cells. Several autophagy biochemical markers including LC3-II conversion, increased punctuate distribution of GFP-LC3 and development of acidic vesicular organelles (AVO) were detected in cells treated with LT. Analysis of individual LT component revealed a moderate increase in LC3-II conversion for protective antigen-treated cells, whereas the LC3-II level in lethal factor-treated cells remained unchanged. Moreover, our preliminary findings suggest a protective role of autophagy in LT intoxication as indicated by accelerated cell death when autophagy was inhibited. Separately, LT was also shown to induce harmful levels of reactive oxygen species (ROS) in immune cells although antioxidant appeared to have some protective effects against its damaging effects. In addition, chemotaxis analysis revealed that LT not only fail to elicit chemokines production in immune cells but also suppressed the chemokines-inducing properties of lipopolysaccharides (LPS) and bacterial cell wall (CW). The wide array of effects that LT exerts on various immune cells reflects the intricacies of the intoxication mechanisms. These findings enhance our understanding of anthrax pathogenesis and may prove to be relevant to the development of a more effective countermeasure against anthrax.



Bacillus anthracis, Autophagy, Protective antigen, Anthrax, Lethal toxin