Why put yourself on a pedestal? The pathogenic role of the A/E pedestal

Abstract

The study of enterobacterial pathogens is of critical importance, given the nearly 63,000 annual diarrheagenic Escherichia coli (E. coli)-related deaths worldwide (1, 2). In particular, enteropathogenic E. coli (EPEC) is a leading cause of infantile diarrhea, often contracted through the fecal-oral route via food or water (3). Attaching and effacing (A/E) pathogens, like EPEC, are named for their signature lesion on the intestinal epithelium during infection. The characteristics of these attaching and effacing lesions are effacement of the intestinal brush border, intimate attachment to the host epithelium, and the formation of actin-rich pedestals below the site of bacterial adherence. These pedestals are derived from bacterial-driven actin nucleation inside the host cell, creating a protrusion in the plasma membrane. Enterohemorrhagic E. coli (EHEC) is another human A/E pathogen that is similar to EPEC but can be distinguished from EPEC by its pathogenic and geographic features. Although EPEC is prevalent in low- and middle-income countries, EHEC is pervasive in developed countries. EPEC preferentially infects the small intestine, and EHEC preferentially infects the colon. Additionally, only EHEC produces Shiga toxin (Stx) that can inhibit protein synthesis in eukaryotic cells and is a cause of many of the systemic symptoms experienced, including long-term renal damage and hemolytic uremic syndrome (4, 5). Regardless of their clinical differences, both EPEC and EHEC are often studied using the murine pathogen Citrobacter rodentium (C. rodentium) as a proxy (6–8). All three pathogens encode the Locus of enterocyte effacement (LEE) pathogenicity island, which encodes a type III secretion system and is required for virulence. C. rodentium possesses the same LEE pathogenicity island-encoded effectors that are required for EPEC and EHEC virulence (9–11). However, the three AE pathogens have other effectors that are not a part of the LEE pathogenicity island, contributing to distinct characteristics in each pathogen. These A/E lesion pathogens are a continuous object of study due, in part, to their unique ability to form pedestals and the unknown role the pedestals play in infection.