Chapter 10 : Direct Penetration of Bacterial Toxins across the Plasma Membrane

Abstract:

Adenylate (or adenylyl) cyclase (AC) toxin is an essential virulence factor for Bordetella pertussis, as mutants lacking this molecule are virtually avirulent in an animal infection model. Receptor-mediated endocytosis (RME) is characterized by several features that can be used to determine whether a particular toxin is entering by that pathway. First, it is generally true that ligand binding can occur at 4 and 37°C, but internalization only occurs at 37°C. Second, binding is saturable and limited by the number of receptor molecules on the target cell. Third, toxins that enter target cells by RME exhibit a lag phase between toxin addition and biological effects, due to the time necessary for uptake into an endosome, acidification of the endosome, and resultant translocation of the catalytic portion into the cytoplasm. All toxins that act on intracellular targets must have a mechanism by which at least a part of their structure can traverse the plasma membrane of the host cell. Divalent metal binding to AC toxin and the membrane potential of the target cell are clearly critical factors in the processes of insertion and translocation of the toxin, but the signals that initiate this sequence of events from the cell surface remain unknown. Most of the understanding of the structure and function of AC toxin comes from work utilizing soluble material obtained by urea extraction of B. pertussis organisms or recombinant Escherichia coli expressing AC toxin. Infection with B. pertussis is not systemic; organisms remain localized to the respiratory mucosa.