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Enterococci: From Commensals to Leading Causes of Drug Resistant Infection

Title:		Transcriptional and Post Transcriptional Control of Enterococcal Gene Regulation
Author(s):		DebRoy S; Gao P; Garsin DA; Harvey BR; Kos V; Nes IF; Solheim M;
Address:		"Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA Center for Molecular Imaging, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Division of Applied Biologics, The University of Texas Health Science Center at Houston, Texas, USA Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA; Center for Molecular Imaging, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Division of Applied Biologics, The University of Texas Health Science Center at Houston, Texas, USA Departments of Ophthalmology and of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA Department of Chemistry, Biotechnology and Food Science, The Norwegian University of Life Sciences, Aas, Norway"
Journal Title:		Enterococci: From Commensals to Leading Causes of Drug Resistant Infection
Year:		2014
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Page Number:		-
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Abstract:		"Enterococci are a versatile group of bacteria found in various habitats, which range from a commensal presence within the gastrointestinal tract of mammals and other organisms, to the environment where they have been identified within soil, water, and food supplies. They are also remarkably hardy and are able to withstand drastic changes within their environments, including factors of temperature, salinity, pH, and available nutrients (Klare, Werner, & Witte, 2001). The ability of the enterococci to rapidly respond to growth and environmental conditions is largely achieved by controlling gene expression. In this chapter, we focus on work to date that provides current understanding of the gene regulation mechanisms in Enterococcus faecalis, an opportunist pathogen with intrinsic resistance to many antibiotics and a causative agent of nosocomial urinary tract infections, endocarditis, and bacteremia. Gene regulation in E. faecalis occurs on multiple levels. At the transcriptional level, the initiation of gene transcription is regulated by transcriptional factors which modulate promoter activities. Thanks to advancements in genome sequencing, multiple genomes of enterococcal species have been revealed, which provides the foundation for an understanding of enterococcal gene function and regulation processes. In the case of E. faecalis V583, the genome consists of 3337 open reading frames (ORFs) on the chromosome, as well as three plasmids (Paulsen, et al., 2003). Among these, 145 genes are predicted to encode for transcriptional regulators that belong to different protein families, including Cro/CI, GntR, MerR, and other transcription regulator protein families (Paulsen, et al., 2003). These transcriptional factors affect the expression of their effector genes by binding to the promoter region of these genes and positively or negatively affecting transcription, which subsequently alters the abundance of the specific mRNAs and proteins produced. This chapter discusses the mode of action for several transcriptional factors identified in E. faecalis and the genes that are regulated by them. Another broad set of regulation machinery involved in gene expression are the two component systems that sense extracellular signaling molecules, and regulate target gene expression at the transcription level as a result. A typical two-component system consists of a membrane-associated histidine kinase receptor (sensor HPK) and a cognate response regulator (RR) which functions as a transcriptional factor (Stock, Robinson, & Goudreau, 200). Phosphorylation of the response regulator by the histidine kinase upon specific environmental stimuli alters its ability to bind to the target DNA sequence or interact with other components of the transcription machinery, which in turn regulates gene expression. In E. faecalis V583, at least 15 two-component systems have been identified that play a critical role in E. faecalis' ability to response to a wide variety of stimuli, including quorum signals, antimicrobials, nutrients, serum components, and bile salts (Paulsen, et al., 2003). The mode of function of several two-component systems, including quorum-sensing related Fsr and vancomycin-resistant gene regulators VanRS, are further discussed in detail to demonstrate the ways in which bacteria respond to different environmental stimuli through these signal transduction processes. Other than the typical HPK-RR two-component systems, several other signaling pathways involving transcriptional regulation in E. faecalis have been described, including the sex pheromone signaling pathway and the pathway for cytolysin toxin expression. In both of these systems, expression of the target genes are controlled by the balance of extracellular antagonistic peptide pairs, which are shifted upon the presence of recipient cells or host cells, respectively. Besides transcriptional regulation, control of gene expression can also occur post-transcriptionally through other mechanisms, including mRNA processing, regulation via riboswitches, or modulation by antisense and small regulatory RNA (sRNA). One of the best-studied examples of post-transcriptional regulation is seen in the control of genes involved in ethanolamine utilization (Garsin, 2010). The E. faecalis ethanolamine utilization (eut) genes are encoded in a complex locus of 18 genes, and include structural, enzymatic, and regulatory components. Upregulation of the eut genes is triggered by the presence of two environmental cues-ethanolamine and adenosylcobalamin (AdoCbl). Each of these input signals is perceived and relayed by two different regulatory systems, and synchrony between them is required for expression of the eut genes. Both regulatory systems control gene expression at the post-transcription initiation level, and target nascent RNA instead of DNA. Post-transcriptional regulation also occurs at several levels in the control of conjugation of a pheromone response plasmid as previously discussed, in which antisense RNA plays an important role in transcriptional regulation. This RNA-mediated reciprocal regulation is RNAse III dependent, which demonstrates the importance of RNA processing in gene expression regulation. A similar observation is reported for the gene expression of E. faecalis Ebp pili, which is positively regulated by the novel endo- and exonuclease RNase J2 (Gao, Pinkston, Nallapareddy, van Hoof, Murray, & Harey, 2010). Small regulatory RNAs have recently been identified as important regulatory elements in bacterial gene expression. Recent transcriptomic analysis of E. faecalis sRNA provides valuable information to understand gene regulation through sRNAs. One of the newly identified sRNAs, EF3314_EF3, is potentially involved in the turnover of some abundant proteins, as demonstrated by the DeltaEF3314_EF3315 sRNA mutant, a finding that indicates a novel regulation process (Shioya, et al., 2011)"
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Notes:		"engGilmore, Michael S Clewell, Don B Ike, Yasuyoshi Shankar, Nathan DebRoy, Sruti Gao, Peng Garsin, Danielle A Harvey, Barret R Kos, Veronica Nes, Ingolf F Solheim, Margrete Review Book Chapter"