Portals and Pathways: Principles of Bacterial Toxin Entry into Host Cells

D uring infection, pathogenic microbes actively remodel host cells and tissues to create a more suitable niche for withstanding the rigors of the host environment. One of the most effective remodeling strategies is the generation of protein toxins that modulate important functions of both immune and nonimmune cells. The central importance of toxins to the virulence strategies of pathogens is most poignantly illustrated in diseases such as diphtheria or botulism, where essentially all of the symptoms can be attributed to toxins acting upon their host cells. Many of the most potent bacterial toxins act inside host cells (see table). Their site of action is perhaps not surprising, if one considers that from the perspective of pathogenic microbes, the eukaryotic intracellular environment is a treasure trove of regulatory pathways and networks that are ripe for manipulation. The potency of intracellularly acting toxins is derived, in part, from their mode of action; most are enzymes that catalyze the covalent modification of specific molecular targets. To be successful, however, intracellularly acting toxins must access their substrates inside target cells. This is no small feat, as the eukaryotic plasma membrane is a formidable gatekeeper that effectively restricts macromolecules such as toxins from passing freely into cells. To overcome the membrane barrier, intracellularly acting toxins are either injected directly into host cells by pathogenic microbes or, alternatively, enter cells in a manner that is microbe-independent (Fig. 1). Overall Paradigms of Toxin Entry into Cells