Enteropathogenic and Enterohemorrhagic Escherichia coli Virulence Gene Regulation

Abstract

3Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) cause significant morbidity and mortality worldwide (18,60,63). Though these E. coli pathotypes are genetically related, many features of their epidemiology, their pathogenesis, and the niches they occupy within the human host are unique. EPEC causes profuse watery diarrhea, primarily in children under the age of 2 years, and mostly affects individuals residing in developing countries. In contrast, adults and children infected by EHEC bacteria can suffer from either bloody or nonbloody diarrhea, and in a small percentage of cases a life-threatening complication known as hemolytic uremic syndrome (HUS) occurs. Many patients with HUS experience long-term renal damage, and they often require dialysis or kidney transplantation. EHEC produces Shiga toxins (Stx), which can cause damage to renal endothelial cells, resulting in HUS, while EPEC bacteria do not possess stx (72). EHEC disease appears in primarily industrialized nations yet causes fewer disease outbreaks in developing countries. This observation has been anecdotally attributed to immunological cross-protection from the related EPEC bacteria prevalent in the less developed regions of the world.There are two additional important differences that distinguish these two E. coli pathotypes. Approximately 10 8 to 10 10 EPEC bacteria are necessary to cause infection in adult human volunteers (6, 27), while the infectious dose for EHEC is far less, estimated to be less than 100 CFU (49). Intriguingly, EPEC infects the small intestine; EHEC infects the large bowel, inflicting bloody diarrhea resulting from damage to the colon. Variants of the outer membrane protein intimin, expressed by both pathotypes, have been implicated as contributors to tissue tropism (103), but whether intimin is the initial adhesin and, secondly, whether other factors contribute to the ability of EPEC to recognize the small bowel and of EHEC to colonize the large bowel are not clearly understood. AE. EPEC and EHEC share genetic and phenotypic similarities, most notably the locus of enterocyte effacement (LEE) pathogenicity island (PAI), encoding a type III secretion system (TTSS), and the ability to form attaching and effacing (AE) intestinal lesions, intimate attachment to the host cell, and formation of "pedestals" cupping individual bacteria (86); for recent reviews, see references 12, 60, and 95. The LEE PAI is essential for disease for both EPEC and EHEC bacteria (27,31,105). The EPEC LEE expressed from a multicopy plasmid transformed into a K-12 laboratory strain of E. coli was necessary and sufficient to form the AE phenotype on human epithelial cells in culture (80). In contrast, the EHEC LEE alone was not sufficient to confer the AE phenotype when expressed in a laboratory strain of E. coli (33), suggesting that factors and/or regulatory proteins necessary for this phenotype exist outside the EHEC LEE. Indeed, TccP (Tir-cytoskeletoncoupling protein [also called EspFu], a protein with 24% amino acid identit...

Regulation of virulence by butyrate sensing in enterohaemorrhagic Escherichia coli

“…These genes are encoded in the LEE pathogenicity island, a chromosomal locus in enteropathogenic strains of E. coli. The LEE genes consist of five operons and several cistrons, and their expression is coordinately regulated at the level of transcription (Mellies et al, 2007). The expression of the LEE genes is regulated by a variety of environmental factors through a cascade controlled by two O157-specific virulence regulators.…”

Ler of pathogenic Escherichia coli forms toroidal protein–DNA complexes

“…These include altering the secondary structure of DNA in response to changing environmental conditions, binding of regulatory proteins that can disrupt H-NS-mediated silencing and/or directly stimulate transcription by interacting with RNA polymerase, and the formation of heteromeric complexes between H-NS and H-NS paralogues, which lack DNAbinding motifs and disrupt H-NS function. In EPEC and EHEC, H-NS silences expression of the T3SS, and the Ler protein encoded within the LEE is an important anti-silencer of H-NS (for a review, see Mellies et al, 2007). Ler is a member of the H-NS family of nucleoid-associated proteins, sharing 24 % amino acid identity and 44 % similarity with H-NS of Salmonella .…”

Dual temporal transcription activation mechanisms control cesT expression in enteropathogenic Escherichia coli

“…The LEE-encoded regulator, Ler, acts to derepress H-NS by competing for DNA binding sites and thus promotes gene expression from multiple LEE transcriptional units (Barba et al, 2005;Bustamante et al, 2011;Haack et al, 2003;Mellies et al, 1999;Sperandio et al, 2000;Umanski et al, 2002). Ler is considered to be a global regulator that receives environmental signals and regulatory input from multiple proteins, leading to host colonization (Mellies et al, 2007). In addition, the global regulator LEE activator and repressor proteins, GrlA and GrlR, respectively, influence transcription.…”

“…Regulatory control of the transcriptional units is complex and involves quorum sensing, transcriptional activators, repressors and derepressors (Mellies et al, 2007). The LEE-encoded regulator, Ler, acts to derepress H-NS by competing for DNA binding sites and thus promotes gene expression from multiple LEE transcriptional units (Barba et al, 2005;Bustamante et al, 2011;Haack et al, 2003;Mellies et al, 1999;Sperandio et al, 2000;Umanski et al, 2002).…”