Environment Controls LEE Regulation in Enteropathogenic Escherichia coli

Abstract

Enteropathogenic Escherichia coli (EPEC) is a significant cause of infant morbidity and mortality in developing regions of the world. Horizontally acquired genetic elements encode virulence structures, effectors, and regulators that promote bacterial colonization and disease. One such genetic element, the locus of enterocyte effacement (LEE), encodes the type three secretion system (T3SS) which acts as a bridge between bacterial and host cells to pass effector molecules that exert changes on the host. Due to its importance in EPEC virulence, regulation of the LEE has been of high priority and its investigation has elucidated many virulence regulators, including master regulator of the LEE Ler, H-NS, other nucleoid-associated proteins, GrlA, and PerC. Media type, environmental signals, sRNA signaling, metabolic processes, and stress responses have profound, strain-specific effects on regulators and LEE expression, and thus T3SS formation. Here we review virulence gene regulation in EPEC, which includes approaches for lessening disease by exploiting the elucidated regulatory pathways.

Keywords: EPEC; LEE; envelope stress; environment; metabolism; sRNA; virulence.

FIGURE 1

Enteropathogenic Escherichia coli (EPEC) LEE and pEAF gene regulation is influenced by environmental inputs. The LEE1 operon encodes Ler, which promotes transcription of all operons and auto-represses its own promoter. LEE1 is regulated by a number of nucleoid associated proteins (Ler, H-NS, Hha, Fis, and IHF), pEAF-encoded regulator PerC, LEE-encoded GrlA/GrlR, quorum-sensing factor QseA, BipA, and GrvA. RelA, CpxR, and QseA regulate the per operon on the pEAF, PerA promotes bfp transcription and auto-activates per. Environmental signals are transmitted through phosphorelay systems, sRNAs, stringent responses, quorum-sensing responses, and envelope stress responses to affect transcription of the LEE and pEAF. Arrows indicate transcription/translation promotion, blunt arrows indicate transcription/translation repression; proteins are in ovals; sRNAs are indicated by curvy lines; genetic elements are indicated by thick black arrows; environmental inputs are in red boxes; dashed line indicates indirect regulation.

FIGURE 2

Envelope stress responses disrupt and promote EPEC virulence and colonization. The σ^E and Cpx responses are triggered when EPEC encounters environmental signals. σ^E promotes degP transcription, which degrades host E-cadherin disrupting adherens junctions, and represses LEE1 transcription. σ^E disrupts virulence by decreasing csrA transcription. Phosphorylated CpxR promotes degP, ppiA, and dsbA transcription, and represses perC transcription. Indole at 1.5 mM represses LEE5 transcription and at 50 μM promotes LEE5 transcription. Thin straight arrows indicate transcription promotion; blunt arrows indicate transcription repression; curved arrow indicates enzymatic reaction; bold arrows indicate genetic elements; proteins are in ovals; environmental signals are in boxes.