Erik L. Hewlett, MD

Erik L. Hewlett, MD

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Structure and function of bacterial toxins as probes of cell signaling

The Hewlett research group interest is in bacterial toxins, as biomedical research tools, as well as virulence factors contributing to the pathogenesis of infectious diseases. Specifically, work in the laboratory is directed at the molecular mechanisms of action of anthrax toxins, edema toxin and lethal toxin, and two toxins from Bordetella pertussis, adenylate cyclase (AC) toxin and pertussis toxin. Edema toxin (ET), produced by Bacillus anthracis, is composed of a binding subunit, protective antigen (PA), and the enzymatically active adenylate cyclase, edema factor (EF). Although simplistically this toxin has a similar function to the bordetella AC toxin, namely producing supraphysiologic levels of cyclic AMP from host cell ATP, the functional and consequential differences between the two are just now becoming fully appreciated. For example, bordetella AC toxin elicits apoptotic cytotoxicity in multiple cell types, whereas ET does not, despite also increasing intracellular cAMP levels. Observations such as these are proving very useful in understanding physiologic processes in the biology of normal and cancer cells, quite apart from microbial pathogenesis.

Lethal toxin (LT) is known to cleave one or more MAPK kinases in target cells and to cause cell death, perhaps by a mechanism related to the MAPKK proteolytic cleavage. The molecular mechanism of LT-elicited cell death and the complementary effects of LT and ET are being studied in cultured macrophages, endothelial cells and other cell types. Of particular relevance is the recognition that LT has activity against melanoma cells and it is being evaluated as a potential treatment modality for that cancer and others.

The other toxin on which extensive work has been done in the lab is pertussis toxin (PT), an ADP-ribosyl transferase that covalently modifies a select population of G proteins, resulting in inhibition of their ability to transduce signals from cell surface receptors. PT is a remarkable tool for cell biology and cancer research, enabling characterization and manipulation of receptor-linked pathways.