The RTX Pore-Forming Toxin α-Hemolysin of Uropathogenic Escherichia Coli : Progress and Perspectives

Abstract

Members of the RTX family of protein toxins are functionally conserved among an assortment of bacterial pathogens. By disrupting host cell integrity through their pore-forming and cytolytic activities, this class of toxins allows pathogens to effectively tamper with normal host cell processes, promoting pathogenesis. Here, we focus on the biology of RTX toxins by describing salient properties of a prototype member, α-hemolysin, which is of ten encoded by strains of uropathogenic Escherichia coli. It has long been appreciated that RTX toxins can have distinct effects on host cells aside from outright lysis. Recently, advances in modeling and analysis of host–pathogen interactions have led to novel findings concerning the consequences of pore formation during host–pathogen interactions. We discuss current progress on longstanding questions concerning cell specificity and pore formation, new areas of investigation that involve toxin-mediated perturbations of host cell signaling cascades and perspectives on the future of RTX toxin investigation.

Extra-intestinal pathogenic Escherichia coli (ExPEC): Disease, carriage and clones

“…which cause host uroepithelial injury, cell lysis, and the subsequent release of intra-cellular micronutrients (36)(37)(38).…”

Structure and function of RTX toxins

“…The ehxCABD operon is located on large EHEC virulence plasmids [185][186][187]. Although Shiga toxins are the major virulence factors of EHEC, the contribution of EhxA is likely clinically important, as it is found in all EHEC serogroups that are known to cause the most severe infections in humans, such the O157:H7 serotype [37,184].…”

“…HlyA is by far the most widely studied RTX toxin and many fundamental aspects on the structure and function of this family have been established on this model toxin [1,2,37,176]. It consists of a single polypeptide of 1024 amino acids (110 kDa) that is posttranslationally modified by the fatty acylation of two lysine residues, Lys-564 and Lys-690 [21,22,62,64,188,189].…”

Strengths and Limitations of Model Systems for the Study of Urinary Tract Infections and Related Pathologies

“…1) (96)(97)(98)(99). However, no single set of virulence factors that is required by all UPEC isolates to cause disease has been identified.…”

“…For example, the pore-forming toxin alpha-hemolysin (HlyA), which is produced by about 50% of all UPEC isolates, can promote the lysis of red blood cells, potentially freeing much-needed iron for use by the pathogens (98). Alternatively, at sublytic concentrations, HlyA can inhibit host cell inflammatory and survival pathways and indirectly stimulate the degradation of host cytoskeletal components (98,174,175,242). In wild-type zebrafish, the survival of a reference UPEC isolate known as UTI89 is entirely dependent upon the expression of HlyA (231).…”