Pathogenicity Island of Efaecalis

The E.faecalis pathogenicity island is 153 kbp and encodes 129 predicted ORFs. Present on this element are genes encoding for virulence factors, transposases, transcriptional regulators, and other proteins potentially involved in adaptation to diverse environments. Spread across the pathogenicity island are 11 transposases and insertion elements, with homology to ORFs from other low G+C gram-positive organisms such as E. faecium, S. aureus, Listeria innocua, L. monocytogenes, S. pneumoniae, and S. epidermidis. In addition, the 5' region of the pathogenicity island has extensive nucleotide sequence identity to the pheromone-responsive plasmids pAM373, pCF10, and pAD1 (EF0005-EF0026), suggesting integration of a pheromone-response plasmid. The only transfer-related genes present, however, comprise a TraG-like protein (EF0011) and a region with 87% identity at the nucleotide level to the second transfer origin (oriT) identified in pAD1.

Within the pathogenicity island are the virulence traits, Esp, cytolysin, and aggregation substance. In addition are a number of proteins that may have potential roles in virulence and/or environmental adaptation in E.faecalis. One of these traits is a putative bile salt hydrolase (cbh) (EF0040), which could add a new ecological niche to this E. faecalis strain, perhaps allowing growth in bile-rich environments such as the bile ducts, and therefore potentially giving this strain a competitive advantage. EF0040 has 67% similarity to the Bsh from L. monocytogenes, which is a bile salt hydrolase [122]. In L. monocytogenes, Bsh is a virulence factor and is regulated by the virulence regulator PrfA [122]. In vivo, deletion of this gene results in decreased fecal carriage in guinea pigs, and reduced liver colonization and virulence was noted in a mouse intravenous model [122]. The contribution of cbh to the pathogenesis of enterococcal infections has not yet been investigated.

In terms of adaptation to different environments, in addition to the bile salt hydrolase, the pathogenicity island contains a phosphotransferase system (PTS) (EF0078-EF0081) and adjacent xylose metabolism genes (EF0082-EF0083), potentially allowing growth on xylose. Other metabolism genes include a ketopantoate reductase (EF0037), an ornithine cyclodeaminase (EF0124), a polysaccharide dea-cetylase (EF0108), and a glycosyl hydrolase (EF0077). These pathways may aid survival in nutrient limiting conditions, or in diverse environments. Additional mechanisms to cope with nutrient limiting conditions include a second putative manganese transporter with homology to EfaCBA, and a putative iron transporter (EF0095, EF0096), both of which may aid in survival in vivo.

As previously mentioned, two Gls24-like proteins are present on the pathogenicity island (EF0117 and EF0055). The Gls24 protein has been shown to be induced under certain stress conditions [46], and disruption of gls24 affects virulence in a mouse model [48]. The exact function of Gls24 or its homologues is unknown.

Also potentially involved in stress response is a Dps-family surface protein (EF0119), with closest homology to Lactobacillus rhamnosus. Some members of this protein family have been shown to bind nonspecifically to DNA under starved conditions, protecting it from cleavage by reactive oxygen species [123]. In addition a DNA-J homologue is present (EF0028), and a putative DNA-damage-induci-ble protein (EF0032). Potentially these three proteins may contribute to DNA repair and protection, and may have an important role in bacterial survival in harsh environmental conditions.

Encoded on the pathogenicity island is a putative potassium ABC transporter and a neighboring two-component regulatory system (EF0087-EF0091) with homology to the kdp operon from E. coli [124], but with closer identity to putative homologues in L. innocua. This operon may be involved in stress response to osmotic shock, allowing transport ofpotassium ions.

Other potential genes involved in virulence or environmental adaptation include a putative N-actylmannosamine-6-phosphate epimerase (EF0066), which is part of the N-acetylmannosamine utilization pathway, often found in oropharyngeal pathogens [125]. In addition, a large cell-wall-associated protein is present (EF0109), with a predicted size of 207kDa. This large protein may have a role in colonization or virulence through adhesion or immune evasion, but its role is at present unknown.

Two genes (EF0120 and EF0122) present on the pathogenicity island have homology to IbrB, and IbrA, respectively, from E.coli [126]. In E.coli these proteins are responsible for activation of the otherwise silent phage-derived eib genes, which bind immunoglobin [126]. Interestingly, also on the pathogenicity island is a protein EF0052, with 49% similarity to the nisin-resistance protein from L. lactis subsp. lactis biovar diacetylactis DRC3, which has been demonstrated to be involved in resistance to nisin in this strain [127, 128]. In a study of S. agalactiae virulence using signature-tagged mutagenesis, two attenuated mutants were identified with insertions in an NisR homologue, although the function of this gene has not been characterized [129]. As nisin is a cationic peptide, it is possible that this protein may confer cross-resistance to other cationic peptides such as defen-sins, or bacteriocins produced by other gut bacteria.

140 | 7 Pathogenomics of Enterococcusfaecalis 7.4

Conclusions and Future Perspectives

E.faecalis is a leading cause of nosocomial infection and this is probably associated with its ability both to survive in the hospital environment and also to overcome the harsh conditions associated with colonization and infection. In addition, over a quarter of the genome is mobile and acquired DNA, suggesting that this organism has the ability to rapidly acquire genetic information and evolve to adapt to its environment. The expeditious acquisition and dissemination of antimicrobial resistance in this organism has been previously demonstrated. Although several traits that contribute to virulence have been characterized in E.faecalis, little is known about the function of many of the potential virulence genes encoded both on the chromosome and in the pathogenicity island. The bacterial/host relationship is very complex, and the mechanisms that enterococci use to change from commensal organism to the etiologic agent of disease are not yet fully understood. However, with information from the genome sequence it is now possible to look closer at gene loci that may have important roles in this interaction.

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