Publications by authors named "Pascale Serror"

43 Publications

Increasing incidence of Enterococcus-associated diseases in poultry in France over the past 15 years.

Vet Microbiol 2022 Jun 11;269:109426. Epub 2022 Apr 11.

ANSES, Epidemiology, Health and Welfare Unit, Ploufragan-Plouzané-Niort laboratory, France.

Enterococci are commensal intestinal bacteria and opportunistic pathogens in humans and animals. Enterococcus-associated diseases are an emerging health issue in poultry. The aim of this retrospective study was to assess the occurrence of enterococci in poultry in France with regard to the manifested diseases and the affected avian species. Our analysis is based on veterinary laboratory data collected by the French poultry epidemiological surveillance network (RNOEA) that monitors avian diseases in France based on the voluntary participation of its veterinarian members. Since the creation of the network in 1989, 12, 177 Enterococcus cases have been reported by veterinary laboratories (Enterococcus cecorum 53.1% and Enterococcus faecalis 24.3%), with emergence starting in 2006, year in which Enterococcus represented 0.4% of all reported pathogens, and incidence growing to 12.9% in 2020. The main diseases associated with these reports were locomotor disorders 35.2% (mainly involving E. cecorum 77.9%), septicaemia 34.9% (involving E. cecorum 53.4% and E. faecalis 23.8%), and omphalitis 14.4% (mainly involving E. faecalis 59.5%). Most of these Enterococcus-associated diseases (71.5%) were reported in broilers (particularly affected by the locomotor disorders and septicaemia involving E. cecorum), accounting for 9.1% of all the diseases reported in this production sector, with an increase from 1.4% in 2006 to 17.2% in 2020. This study highlights the emergence of enterococcal diseases in poultry in France over the past 15 years and the need to maintain a surveillance system.
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http://dx.doi.org/10.1016/j.vetmic.2022.109426DOI Listing
June 2022

The unforeseen intracellular lifestyle of in hepatocytes.

Gut Microbes 2022 Jan-Dec;14(1):2058851

Université -Saclay, Inrae, AgroParisTech, Micalis Institute, Jouy-en-Josas, France.

is a bacterial species present at a subdominant level in the human gut microbiota. This commensal turns into an opportunistic pathogen under specific conditions involving dysbiosis and host immune deficiency. is one of the rare pathobionts identified to date as contributing to liver damage in alcoholic liver disease. We have previously observed that is internalized in hepatocytes. Here, the survival and fate of was examined in hepatocytes, the main epithelial cell type in the liver. Although referred to as an extracellular pathogen, we demonstrate that is able to survive and divide in hepatocytes, and form intracellular clusters in two distinct hepatocyte cell lines, in primary mouse hepatocytes, as well as . This novel process extends to kidney cells. Unraveling the intracellular lifestyle of , our findings contribute to the understanding of pathobiont-driven diseases.
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http://dx.doi.org/10.1080/19490976.2022.2058851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986240PMC
April 2022

An Immunomodulatory Transcriptional Signature Associated With Persistent Infection in Hepatocytes.

Front Cell Infect Microbiol 2021 10;11:761945. Epub 2021 Nov 10.

Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France.

causes severe foodborne illness in pregnant women and immunocompromised individuals. After the intestinal phase of infection, the liver plays a central role in the clearance of this pathogen through its important functions in immunity. However, recent evidence suggests that during long-term infection of hepatocytes, a subpopulation of may escape eradication by entering a persistence phase in intracellular vacuoles. Here, we examine whether this long-term infection alters hepatocyte defense pathways, which may be instrumental for bacterial persistence. We first optimized cell models of persistent infection in human hepatocyte cell lines HepG2 and Huh7 and primary mouse hepatocytes (PMH). In these cells, efficiently entered the persistence phase after three days of infection, while inducing a potent interferon response, of type I in PMH and type III in HepG2, while Huh7 remained unresponsive. RNA-sequencing analysis identified a common signature of long-term infection characterized by the overexpression of a set of genes involved in antiviral immunity and the under-expression of many acute phase protein (APP) genes, particularly involved in the complement and coagulation systems. Infection also altered the expression of cholesterol metabolism-associated genes in HepG2 and Huh7 cells. The decrease in APP transcripts was correlated with lower protein abundance in the secretome of infected cells, as shown by proteomics, and also occurred in the presence of APP inducers (IL-6 or IL-1β). Collectively, these results reveal that long-term infection with profoundly deregulates the innate immune functions of hepatocytes, which could generate an environment favorable to the establishment of persistent infection.
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http://dx.doi.org/10.3389/fcimb.2021.761945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631403PMC
January 2022

Commensal bacteria augment Staphylococcus aureus infection by inactivation of phagocyte-derived reactive oxygen species.

PLoS Pathog 2021 09 16;17(9):e1009880. Epub 2021 Sep 16.

Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom.

Staphylococcus aureus is a human commensal organism and opportunist pathogen, causing potentially fatal disease. The presence of non-pathogenic microflora or their components, at the point of infection, dramatically increases S. aureus pathogenicity, a process termed augmentation. Augmentation is associated with macrophage interaction but by a hitherto unknown mechanism. Here, we demonstrate a breadth of cross-kingdom microorganisms can augment S. aureus disease and that pathogenesis of Enterococcus faecalis can also be augmented. Co-administration of augmenting material also forms an efficacious vaccine model for S. aureus. In vitro, augmenting material protects S. aureus directly from reactive oxygen species (ROS), which correlates with in vivo studies where augmentation restores full virulence to the ROS-susceptible, attenuated mutant katA ahpC. At the cellular level, augmentation increases bacterial survival within macrophages via amelioration of ROS, leading to proliferation and escape. We have defined the molecular basis for augmentation that represents an important aspect of the initiation of infection.
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http://dx.doi.org/10.1371/journal.ppat.1009880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478205PMC
September 2021

Complete Structure of the Enterococcal Polysaccharide Antigen (EPA) of Vancomycin-Resistant Enterococcus faecalis V583 Reveals that EPA Decorations Are Teichoic Acids Covalently Linked to a Rhamnopolysaccharide Backbone.

mBio 2020 04 28;11(2). Epub 2020 Apr 28.

Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France

All enterococci produce a complex polysaccharide called the nterococcal olysaccharide ntigen (EPA). This polymer is required for normal cell growth and division and for resistance to cephalosporins and plays a critical role in host-pathogen interaction. The EPA contributes to host colonization and is essential for virulence, conferring resistance to phagocytosis during the infection. Recent studies revealed that the "decorations" of the EPA polymer, encoded by genetic loci that are variable between isolates, underpin the biological activity of this surface polysaccharide. In this work, we investigated the structure of the EPA polymer produced by the high-risk enterococcal clonal complex V583. We analyzed purified EPA from the wild-type strain and a mutant lacking decorations and elucidated the structure of the EPA backbone and decorations. We showed that the rhamnan backbone of EPA is composed of a hexasaccharide repeat unit of C2- and C3-linked rhamnan chains, partially substituted in the C3 position by α-glucose (α-Glc) and in the C2 position by β--acetylglucosamine (β-GlcNAc). The so-called "EPA decorations" consist of phosphopolysaccharide chains corresponding to teichoic acids covalently bound to the rhamnan backbone. The elucidation of the complete EPA structure allowed us to propose a biosynthetic pathway, a first essential step toward the design of antimicrobials targeting the synthesis of this virulence factor. Enterococci are opportunistic pathogens responsible for hospital- and community-acquired infections. All enterococci produce a surface polysaccharide called EPA (nterococcal olysaccharide ntigen) required for biofilm formation, antibiotic resistance, and pathogenesis. Despite the critical role of EPA in cell growth and division and as a major virulence factor, no information is available on its structure. Here, we report the complete structure of the EPA polymer produced by the model strain V583. We describe the structure of the EPA backbone, made of a rhamnan hexasaccharide substituted by Glc and GlcNAc residues, and show that teichoic acids are covalently bound to this rhamnan chain, forming the so-called "EPA decorations" essential for host colonization and pathogenesis. This report represents a key step in efforts to identify the structural properties of EPA that are essential for its biological activity and to identify novel targets to develop preventive and therapeutic approaches against enterococci.
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http://dx.doi.org/10.1128/mBio.00277-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188991PMC
April 2020

Dynamic insights on transcription initiation and RNA processing during bacterial adaptation.

RNA 2020 04 28;26(4):382-395. Epub 2020 Jan 28.

Université Paris-Saclay, INRAE, AgroParisTech, MIcalis Institute, 78350, Jouy-en-Josas, France.

Transcription initiation and RNA processing govern gene expression and enable bacterial adaptation by reshaping the RNA landscape. The aim of this study was to simultaneously observe these two fundamental processes in a transcriptome responding to an environmental signal. A controlled σ system in was coupled to our previously described tagRNA-seq method to yield process kinetics information. Changes in transcription initiation frequencies (TIF) and RNA processing frequencies (PF) were followed using 5' RNA tags. Changes in TIF showed a binary increased/decreased pattern that alternated between transcriptionally activated and repressed promoters, providing the bacterial population with transcriptional oscillation. PF variation fell into three categories of cleavage activity: (i) constant and independent of RNA levels, (ii) increased once RNA has accumulated, and (iii) positively correlated to changes in TIF. This work provides a comprehensive and dynamic view of major events leading to transcriptomic reshaping during bacterial adaptation. It unveils an interplay between transcription initiation and the activity of specific RNA cleavage sites. This study utilized a well-known genetic system to analyze fundamental processes and can serve as a blueprint for comprehensive studies that exploit the RNA metabolism to decipher and understand bacterial gene expression control.
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http://dx.doi.org/10.1261/rna.073288.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075262PMC
April 2020

Fitness Restoration of a Genetically Tractable Enterococcus faecalis V583 Derivative To Study Decoration-Related Phenotypes of the Enterococcal Polysaccharide Antigen.

mSphere 2019 07 10;4(4). Epub 2019 Jul 10.

UMR Micalis, INRA, AgroParisTech, Université Paris-Saclay, UMR1319, Jouy-en-Josas, France

Commensal and generally harmless in healthy individuals, causes opportunistic infections in immunocompromised patients. Plasmid-cured strain VE14089, derived from sequenced reference strain V583, is widely used for functional studies due to its improved genetic amenability. Although strain VE14089 has no major DNA rearrangements, with the exception of an ∼20-kb integrated region of pTEF1 plasmid, the strain presented significant growth differences from the V583 reference strain of our collection (renamed VE14002). In the present study, genome sequencing of strain VE14089 identified additional point mutations. Excision of the integrated pTEF1 plasmid region and sequential restoration of wild-type alleles showing nonsilent mutations were performed to obtain the VE18379 reference-derivative strain. Recovery of the growth ability of the restored VE18379 strain at a level similar to that seen with the reference strain points to GreA and Spx as bacterial fitness determinants. Virulence potential in and intestinal colonization in mouse demonstrated host adaptation of the VE18379 strain equivalent to VE14002 host adaptation. We further demonstrated that deletion of the 16.8-kb variable region of the locus recapitulates the key role of Epa decoration in host adaptation, providing a genetic system to study the role of specific -variable regions in host adaptation independently of other genetic variations. strain VE14089 was derived from V583 cured of its plasmids. Although VE14089 had no major DNA rearrangements, it presented significant growth and host adaptation differences from the reference strain V583 of our collection. To construct a strain with better fitness, we sequenced the genome of VE14089, identified single nucleotide polymorphisms (SNPs), and repaired the genes that could account for these changes. Using this reference-derivative strain, we provide a novel genetic system to understand the role of the variable region of in the enterococcal lifestyle.
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http://dx.doi.org/10.1128/mSphere.00310-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620374PMC
July 2019

Intestinal translocation of enterococci requires a threshold level of enterococcal overgrowth in the lumen.

Sci Rep 2019 06 20;9(1):8926. Epub 2019 Jun 20.

Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy en Josas, France.

Enterococci are subdominant members of the human gastrointestinal microbiota. Enterococcus faecalis is generally harmless for healthy individuals, but it can cause a diverse range of infections in immunodeficient or elderly patients with severe underlying diseases. In this study, we analysed the levels of intestinal translocation of indigenous enterococci in C57BL/6, CF-1 and CX3CR1 mice upon clindamycin antibiotic-induced dysbiosis. We found that C57BL/6 was the most permissive model for enterococcal translocation and that initiation of E. faecalis translocation coincided with a threshold of enterococcal colonisation in the gut lumen, which once reached, triggered E. faecalis dissemination to deeper organs. We showed that the extent to which E. faecalis clinical strain VE14821 competed with indigenous enterococci differed between the C57BL/6 and CX3CR1 models. Finally, using a simplified gnotobiotic model, we observed E. faecalis crossing an intact intestinal tract using intestinal epithelial cells as one route to reach the lamina propria. Our study opens new perspectives for assessing the effect of various immunodeficiencies and for investigating mechanisms underlying enterococcal translocation.
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http://dx.doi.org/10.1038/s41598-019-45441-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586816PMC
June 2019

Binding activity to intestinal cells and transient colonization in mice of two Lactobacillus paracasei subsp. paracasei strains with high aggregation potential.

World J Microbiol Biotechnol 2019 May 27;35(6):85. Epub 2019 May 27.

Laboratory for Molecular Microbiology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444/a, P.O. Box 23, Belgrade, 11010, Serbia.

Surface properties like hydrophobicity, aggregation ability, adhesion to mucosal surfaces and epithelial cells and transit time are key features for the characterization of probiotic strains. In this study, we used two Lactobacillus paracasei subsp. paracasei strains (BGNJ1-64 and BGSJ2-8) strains which were previously described with very strong aggregation capacity. The aggregation promoting factor (AggLb) expressed in these strains showed high level of binding to collagen and fibronectin, components of extracellular matrix. The working hypothesis was that strains able to aggregate have an advantage to resist in intestinal tract. So, we assessed whether these strains and their derivatives (without aggLb gene) are able to bind or not to intestinal components and we compared the transit time of each strains in mice. In that purpose parental strains (BGNJ1-64 and BGSJ2-8) and their aggregation negative derivatives (BGNJ1-641 and BGSJ2-83) were marked with double antibiotic resistance in order to be tracked in in vivo experiments in mice. Comparative analysis of binding ability of WT and aggregation negative strains to different human intestinal cell lines and mucin revealed no significant difference among them, excluding involvement of AggLb in interaction with surface of intestinal cells and mucin. In vivo experiments showed that surviving and transit time of marked strains in mice did not drastically depend on the presence of the AggLb aggregation factor.
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http://dx.doi.org/10.1007/s11274-019-2663-4DOI Listing
May 2019

Decoration of the enterococcal polysaccharide antigen EPA is essential for virulence, cell surface charge and interaction with effectors of the innate immune system.

PLoS Pathog 2019 05 2;15(5):e1007730. Epub 2019 May 2.

Krebs Institute, University of Sheffield, Firth Court, Western Bank, Sheffield, United Kingdom.

Enterococcus faecalis is an opportunistic pathogen with an intrinsically high resistance to lysozyme, a key effector of the innate immune system. This high level of resistance requires a complex network of transcriptional regulators and several genes (oatA, pgdA, dltA and sigV) acting synergistically to inhibit both the enzymatic and cationic antimicrobial peptide activities of lysozyme. We sought to identify novel genes modulating E. faecalis resistance to lysozyme. Random transposon mutagenesis carried out in the quadruple oatA/pgdA/dltA/sigV mutant led to the identification of several independent insertions clustered on the chromosome. These mutations were located in a locus referred to as the enterococcal polysaccharide antigen (EPA) variable region located downstream of the highly conserved epaA-epaR genes proposed to encode a core synthetic machinery. The epa variable region was previously proposed to be responsible for EPA decorations, but the role of this locus remains largely unknown. Here, we show that EPA decoration contributes to resistance towards charged antimicrobials and underpins virulence in the zebrafish model of infection by conferring resistance to phagocytosis. Collectively, our results indicate that the production of the EPA rhamnopolysaccharide backbone is not sufficient to promote E. faecalis infections and reveal an essential role of the modification of this surface polymer for enterococcal pathogenesis.
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http://dx.doi.org/10.1371/journal.ppat.1007730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497286PMC
May 2019

Countermeasures Defeat a Virulent Bacteriophage.

Viruses 2019 01 10;11(1). Epub 2019 Jan 10.

Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France.

is an opportunistic pathogen that has emerged as a major cause of nosocomial infections worldwide. Many clinical strains are indeed resistant to last resort antibiotics and there is consequently a reawakening of interest in exploiting virulent phages to combat them. However, little is still known about phage receptors and phage resistance mechanisms in enterococci. We made use of a prophageless derivative of the well-known clinical strain V583 to isolate a virulent phage belonging to the subfamily and to the P68 genus that we named Idefix. Interestingly, most isolates of tested-including V583-were resistant to this phage and we investigated more deeply into phage resistance mechanisms. We found that V583 prophage 6 was particularly efficient in resisting Idefix infection thanks to a new abortive infection (Abi) mechanism, which we designated Abiα. It corresponded to the Pfam domain family with unknown function DUF4393 and conferred a typical Abi phenotype by causing a premature lysis of infected . The gene is widespread among prophages of enterococci and other Gram-positive bacteria. Furthermore, we identified two genes involved in the synthesis of the side chains of the surface rhamnopolysaccharide that are important for Idefix adsorption. Interestingly, mutants in these genes arose at a frequency of ~10 resistant mutants per generation, conferring a supplemental bacterial line of defense against Idefix.
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http://dx.doi.org/10.3390/v11010048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356687PMC
January 2019

Lactobacillus paracasei CNCM I-3689 reduces vancomycin-resistant Enterococcus persistence and promotes Bacteroidetes resilience in the gut following antibiotic challenge.

Sci Rep 2018 03 23;8(1):5098. Epub 2018 Mar 23.

Micalis, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.

Enterococci, in particular vancomycin-resistant enterococci (VRE), are a leading cause of hospital-acquired infections. Promoting intestinal resistance against enterococci could reduce the risk of VRE infections. We investigated the effects of two Lactobacillus strains to prevent intestinal VRE. We used an intestinal colonisation mouse model based on an antibiotic-induced microbiota dysbiosis to mimic enterococci overgrowth and VRE persistence. Each Lactobacillus spp. was administered daily to mice starting one week before antibiotic treatment until two weeks after antibiotic and VRE inoculation. Of the two strains, Lactobacillus paracasei CNCM I-3689 decreased significantly VRE numbers in the feces demonstrating an improvement of the reduction of VRE. Longitudinal microbiota analysis showed that supplementation with L. paracasei CNCM I-3689 was associated with a better recovery of members of the phylum Bacteroidetes. Bile salt analysis and expression analysis of selected host genes revealed increased level of lithocholate and of ileal expression of camp (human LL-37) upon L. paracasei CNCM I-3689 supplementation. Although a direct effect of L. paracasei CNCM I-3689 on the VRE reduction was not ruled out, our data provide clues to possible anti-VRE mechanisms supporting an indirect anti-VRE effect through the gut microbiota. This work sustains non-antibiotic strategies against opportunistic enterococci after antibiotic-induced dysbiosis.
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http://dx.doi.org/10.1038/s41598-018-23437-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865147PMC
March 2018

Surfaceome and Proteosurfaceome in Parietal Monoderm Bacteria: Focus on Protein Cell-Surface Display.

Front Microbiol 2018 14;9:100. Epub 2018 Feb 14.

Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.

The cell envelope of parietal monoderm bacteria (archetypal Gram-positive bacteria) is formed of a cytoplasmic membrane (CM) and a cell wall (CW). While the CM is composed of phospholipids, the CW is composed at least of peptidoglycan (PG) covalently linked to other biopolymers, such as teichoic acids, polysaccharides, and/or polyglutamate. Considering the CW is a porous structure with low selective permeability contrary to the CM, the bacterial cell surface hugs the molecular figure of the CW components as a well of the external side of the CM. While the surfaceome corresponds to the totality of the molecules found at the bacterial cell surface, the proteinaceous complement of the surfaceome is the proteosurfaceome. Once translocated across the CM, secreted proteins can either be released in the extracellular milieu or exposed at the cell surface by associating to the CM or the CW. Following the gene ontology (GO) for cellular components, cell-surface proteins at the CM can either be integral (GO: 0031226), i.e., the integral membrane proteins, or anchored to the membrane (GO: 0046658), i.e., the lipoproteins. At the CW (GO: 0009275), cell-surface proteins can be covalently bound, i.e., the LPXTG-proteins, or bound through weak interactions to the PG or wall polysaccharides, i.e., the cell wall binding proteins. Besides monopolypeptides, some proteins can associate to each other to form supramolecular protein structures of high molecular weight, namely the S-layer, pili, flagella, and cellulosomes. After reviewing the cell envelope components and the different molecular mechanisms involved in protein attachment to the cell envelope, perspectives in investigating the proteosurfaceome in parietal monoderm bacteria are further discussed.
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http://dx.doi.org/10.3389/fmicb.2018.00100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817068PMC
February 2018

Exploration of the role of the virulence factor ElrA during Enterococcus faecalis cell infection.

Sci Rep 2018 01 29;8(1):1749. Epub 2018 Jan 29.

Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy en Josas, France.

Enterococcus faecalis, an organism generally not pathogenic for healthy humans, has the potential to cause disease in susceptible hosts. While it seems to be equipped to interact with and circumvent host immune defense, most of the molecular and cellular mechanisms underlying the enterococcal infectious process remain elusive. Here, we investigated the role of the Enterococcal Leucine Rich protein A (ElrA), an internalin-like protein of E. faecalis also known as a virulence factor. ElrA was previously shown to prevent adhesion to macrophages. We show that ElrA does not inhibit the basic phagocytic process, but is able to prevent sensing and migration of macrophages toward E. faecalis. Presence or absence of FHL2, a eukaryotic partner of ElrA, does not affect the ElrA-dependent mechanism preventing macrophage migration. However, we highlight a partial contribution of FHL2 in ElrA-mediated virulence in vivo. Our results indicate that ElrA plays at least a dual role of which anti-phagocytic activity may contribute to dissemination of extracellular E. faecalis during infection.
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http://dx.doi.org/10.1038/s41598-018-20206-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788860PMC
January 2018

Three glycosylated serine-rich repeat proteins play a pivotal role in adhesion and colonization of the pioneer commensal bacterium, Streptococcus salivarius.

Environ Microbiol 2017 09 24;19(9):3579-3594. Epub 2017 Jul 24.

STLO, UMR1253, INRA, Agrocampus Ouest, Rennes, France.

Bacterial adhesion is a critical step for colonization of the host. The pioneer colonizer and commensal bacterium of the human gastrointestinal tract, Streptococcus salivarius, has strong adhesive properties but the molecular determinants of this adhesion remain uncharacterized. Serine-rich repeat (SRR) glycoproteins are a family of adhesins that fulfil an important role in adhesion. In general, Gram-positive bacterial genomes have a unique SRR glycoprotein-encoding gene. We demonstrate that S. salivarius expresses three large and glycosylated surface-exposed proteins - SrpA, SrpB and SrpC - that show characteristics of SRR glycoproteins and are secreted through the accessory SecA2/Y2 system. Two glycosyltransferases - GtfE/F - encoded outside of the secA2/Y2 locus, unusually, perform the first step of the sequential glycosylation process, which is crucial for SRR activity. We show that SrpB and SrpC play complementary adhesive roles involved in several steps of the colonization process: auto-aggregation, biofilm formation and adhesion to a variety of host epithelial cells and components. We also show that at least one of the S. salivarius SRR glycoproteins is important for colonization in mice. SrpA, SrpB and SrpC are the main factors underlying the multifaceted adhesion of S. salivarius and, therefore, play a major role in host colonization.
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http://dx.doi.org/10.1111/1462-2920.13853DOI Listing
September 2017

The Enterococcus faecalis virulence factor ElrA interacts with the human Four-and-a-Half LIM Domains Protein 2.

Sci Rep 2017 07 4;7(1):4581. Epub 2017 Jul 4.

Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, 78350, Jouy-en-Josas, France.

The commensal bacterium Enterococcus faecalis is a common cause of nosocomial infections worldwide. The increasing prevalence of multi-antibiotic resistant E. faecalis strains reinforces this public health concern. Despite numerous studies highlighting several pathology-related genetic traits, the molecular mechanisms of E. faecalis virulence remain poorly understood. In this work, we studied 23 bacterial proteins that could be considered as virulence factors or involved in the Enterococcus interaction with the host. We systematically tested their interactions with human proteins using the Human ORFeome library, a set of 12,212 human ORFs, in yeast. Among the thousands of tested interactions, one involving the E. faecalis virulence factor ElrA and the human protein FHL2 was evidenced by yeast two-hybrid and biochemically confirmed. Further molecular characterizations allowed defining an FHL2-interacting domain (FID) of ElrA. Deletion of the FID led to an attenuated in vivo phenotype of the mutated strain clearly indicating that this interaction is likely to contribute to the multifactorial virulence of this opportunistic pathogen. Altogether, our results show that FHL2 is the first host cellular protein directly targeted by an E. faecalis virulence factor and that this interaction is involved in Enterococcus pathogenicity.
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http://dx.doi.org/10.1038/s41598-017-04875-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496941PMC
July 2017

Regulatory crosstalk between type I and type II toxin-antitoxin systems in the human pathogen Enterococcus faecalis.

RNA Biol 2015 25;12(10):1099-108. Epub 2015 Aug 25.

a INRA UMR1319 Micalis ; Jouy-en-Josas , France.

We discovered a chromosomal locus containing 2 toxin-antitoxin modules (TAs) with an antisense transcriptional organization in the E. faecalis clinical isolate V583. These TAs are homologous to the type I txpA-ratA system and the type II mazEF, respectively. We have shown that the putative MazF is toxic for E. coli and triggers RNA degradation, and its cognate antitoxin MazE counteracts toxicity. The second module, adjacent to mazEF, expresses a toxin predicted to belong to the TxpA type I family found in Firmicutes, and the antisense RNA antidote, RatA. Genomic analysis indicates that the cis-association of mazEF and txpA-ratA modules has been favored during evolution, suggesting a selective advantage for this TA organization in the E. faecalis species. We showed regulatory interplays between the 2 modules, involving transcription control and RNA stability. Remarkably, our data reveal that MazE and MazEF have a dual transcriptional activity: they act as autorepressors and activate ratA transcription, most likely in a direct manner. RatA controls txpA RNA levels through stability. Our data suggest a pivotal role of MazEF in the coordinated expression of mazEF and txpA-ratA modules in V583. To our knowledge, this is the first report describing a crosstalk between type I and II TAs.
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http://dx.doi.org/10.1080/15476286.2015.1084465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829291PMC
May 2016

Overexpression of Enterococcus faecalis elr operon protects from phagocytosis.

BMC Microbiol 2015 May 25;15:112. Epub 2015 May 25.

INRA, UMR1319 Micalis, Jouy-en-Josas, France.

Background: Mechanisms underlying the transition from commensalism to virulence in Enterococcus faecalis are not fully understood. We previously identified the enterococcal leucine-rich protein A (ElrA) as a virulence factor of E. faecalis. The elrA gene is part of an operon that comprises four other ORFs encoding putative surface proteins of unknown function.

Results: In this work, we compared the susceptibility to phagocytosis of three E. faecalis strains, including a wild-type (WT), a ΔelrA strain, and a strain overexpressing the whole elr operon in order to understand the role of this operon in E. faecalis virulence. While both WT and ΔelrA strains were efficiently phagocytized by RAW 264.7 mouse macrophages, the elr operon-overexpressing strain showed a decreased capability to be internalized by the phagocytic cells. Consistently, the strain overexpressing elr operon was less adherent to macrophages than the WT strain, suggesting that overexpression of the elr operon could confer E. faecalis with additional anti-adhesion properties. In addition, increased virulence of the elr operon-overexpressing strain was shown in a mouse peritonitis model.

Conclusions: Altogether, our results indicate that overexpression of the elr operon facilitates the E. faecalis escape from host immune defenses.
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http://dx.doi.org/10.1186/s12866-015-0448-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522977PMC
May 2015

Whole-genome mapping of 5' RNA ends in bacteria by tagged sequencing: a comprehensive view in Enterococcus faecalis.

RNA 2015 May 3;21(5):1018-30. Epub 2015 Mar 3.

Department of Computational Biology, KTH Royal Institute of Technology, AlbaNova University Center, SE-10691 Stockholm, Sweden Department of Information and Computer Science, Aalto University, FI-02150 Espoo, Finland.

Enterococcus faecalis is the third cause of nosocomial infections. To obtain the first snapshot of transcriptional organizations in this bacterium, we used a modified RNA-seq approach enabling to discriminate primary from processed 5' RNA ends. We also validated our approach by confirming known features in Escherichia coli. We mapped 559 transcription start sites (TSSs) and 352 processing sites (PSSs) in E. faecalis. A blind motif search retrieved canonical features of SigA- and SigN-dependent promoters preceding transcription start sites mapped. We discovered 85 novel putative regulatory RNAs, small- and antisense RNAs, and 72 transcriptional antisense organizations. Presented data constitute a significant insight into bacterial RNA landscapes and a step toward the inference of regulatory processes at transcriptional and post-transcriptional levels in a comprehensive manner.
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http://dx.doi.org/10.1261/rna.048470.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408782PMC
May 2015

Potential use of probiotic and commensal bacteria as non-antibiotic strategies against vancomycin-resistant enterococci.

FEMS Microbiol Lett 2015 Apr 8;362(8):fnv012. Epub 2015 Feb 8.

INRA, UMR1319 Micalis, F-78350 Jouy-en-Josas, France; and AgroParisTech, UMR Micalis, F-78350 Jouy-en-Josas, France

Vancomycin-resistant enterococci (VRE) represent major opportunistic pathogens in immunocompromised populations. Particularly adapted to the hospital environment, VRE efficiently colonize the gastrointestinal (GI) tract of patients. Furthermore, certain circumstances of antibiotic-induced dysbiosis of the gut microbiota contribute to colonization, overgrowth and persistence of VRE in the GI tract, increasing the risk of infection in critically ill and/or severally immunocompromised patients. VRE treatment with antibiotics remains challenging due to the robustness and ability of enterococci to adapt to harsh conditions and to acquire novel resistance genes. Reducing VRE intestinal colonization, overgrowth and carriage has thus become an important issue to reduce the risk of infection and dissemination. This review summarizes the knowledge of the conditions favoring VRE colonization and persistence in the GI tract and focuses on the strategies to reduce overgrowth or persistence of VRE in the GI tract based on the oral administration of probiotic or commensal bacteria in human studies and in animal models, and on the potential underlying mechanisms of the anti-VRE effect.
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http://dx.doi.org/10.1093/femsle/fnv012DOI Listing
April 2015

The surface rhamnopolysaccharide epa of Enterococcus faecalis is a key determinant of intestinal colonization.

J Infect Dis 2015 Jan 17;211(1):62-71. Epub 2014 Jul 17.

INRA, UMR1319 Micalis AgroParisTech, UMR Micalis, Jouy-en-Josas, France.

Enterococcus faecalis is a commensal bacterium of the human intestine and a major opportunistic pathogen in immunocompromised and elderly patients. The pathogenesis of E. faecalis infection relies in part on its capacity to colonize the gut. Following disruption of intestinal homeostasis, E. faecalis can overgrow, cross the intestinal barrier, and enter the lymph and bloodstream. To identify and characterize E. faecalis genes that are key to intestinal colonization, our strategy consisted in screening mutants for the following phenotypes related to intestinal lifestyle: antibiotic resistance, overgrowth, and competition against microbiota. From the identified colonization genes, epaX encodes a glycosyltransferase located in a variable region of the enterococcal polysaccharide antigen (epa) locus. We demonstrated that EpaX acts on sugar composition, promoting resistance to bile salts and cell wall integrity. Given that EpaX is enriched in hospital-adapted isolates, this study points to the importance of the epa variability as a key determinant for enterococcal intestinal colonization.
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http://dx.doi.org/10.1093/infdis/jiu402DOI Listing
January 2015

Zebrafish as a novel vertebrate model to dissect enterococcal pathogenesis.

Infect Immun 2013 Nov 3;81(11):4271-9. Epub 2013 Sep 3.

Krebs Institute, University of Sheffield, Sheffield, United Kingdom.

Enterococcus faecalis is an opportunistic pathogen responsible for a wide range of life-threatening nosocomial infections, such as septicemia, peritonitis, and endocarditis. E. faecalis infections are associated with a high mortality and substantial health care costs and cause therapeutic problems due to the intrinsic resistance of this bacterium to antibiotics. Several factors contributing to E. faecalis virulence have been identified. Due to the variety of infections caused by this organism, numerous animal models have been used to mimic E. faecalis infections, but none of them is considered ideal for monitoring pathogenesis. Here, we studied for the first time E. faecalis pathogenesis in zebrafish larvae. Using model strains, chosen isogenic mutants, and fluorescent derivatives expressing green fluorescent protein (GFP), we analyzed both lethality and bacterial dissemination in infected larvae. Genetically engineered immunocompromised zebrafish allowed the identification of two critical steps for successful establishment of disease: (i) host phagocytosis evasion mediated by the Epa rhamnopolysaccharide and (ii) tissue damage mediated by the quorum-sensing Fsr regulon. Our results reveal that the zebrafish is a novel, powerful model for studying E. faecalis pathogenesis, enabling us to dissect the mechanism of enterococcal virulence.
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http://dx.doi.org/10.1128/IAI.00976-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811811PMC
November 2013

Enterococcus faecalis prophage dynamics and contributions to pathogenic traits.

PLoS Genet 2013 Jun 6;9(6):e1003539. Epub 2013 Jun 6.

INRA, UMR1319 Micalis, Jouy-en-Josas, France.

Polylysogeny is frequently considered to be the result of an adaptive evolutionary process in which prophages confer fitness and/or virulence factors, thus making them important for evolution of both bacterial populations and infectious diseases. The Enterococcus faecalis V583 isolate belongs to the high-risk clonal complex 2 that is particularly well adapted to the hospital environment. Its genome carries 7 prophage-like elements (V583-pp1 to -pp7), one of which is ubiquitous in the species. In this study, we investigated the activity of the V583 prophages and their contribution to E. faecalis biological traits. We systematically analyzed the ability of each prophage to excise from the bacterial chromosome, to replicate and to package its DNA. We also created a set of E. faecalis isogenic strains that lack from one to all six non-ubiquitous prophages by mimicking natural excision. Our work reveals that prophages of E. faecalis V583 excise from the bacterial chromosome in the presence of a fluoroquinolone, and are able to produce active phage progeny. Intricate interactions between V583 prophages were also unveiled: i) pp7, coined EfCIV583 for E. faecalis chromosomal island of V583, hijacks capsids from helper phage 1, leading to the formation of distinct virions, and ii) pp1, pp3 and pp5 inhibit excision of pp4 and pp6. The hijacking exerted by EfCIV583 on helper phage 1 capsids is the first example of molecular piracy in Gram positive bacteria other than staphylococci. Furthermore, prophages encoding platelet-binding-like proteins were found to be involved in adhesion to human platelets, considered as a first step towards the development of infective endocarditis. Our findings reveal not only a role of E. faecalis V583 prophages in pathogenicity, but also provide an explanation for the correlation between antibiotic usage and E. faecalis success as a nosocomial pathogen, as fluoriquinolone may provoke release of prophages and promote gene dissemination among isolates.
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http://dx.doi.org/10.1371/journal.pgen.1003539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675006PMC
June 2013

Enterococcal Rgg-like regulator ElrR activates expression of the elrA operon.

J Bacteriol 2013 Jul 3;195(13):3073-83. Epub 2013 May 3.

INRA, UMR1319 Micalis, Jouy-en-Josas, France.

The Enterococcus faecalis leucine-rich protein ElrA promotes virulence by stimulating bacterial persistence in macrophages and production of the interleukin-6 (IL-6) cytokine. The ElrA protein is encoded within an operon that is poorly expressed under laboratory conditions but induced in vivo. In this study, we identify ef2687 (renamed elrR), which encodes a member of the Rgg (regulator gene for glucosyltransferase) family of putative regulatory proteins. Using quantitative reverse transcription-PCR, translational lacZ fusions, and electrophoretic mobility shift assays, we demonstrate that ElrR positively regulates expression of elrA. These results correlate with the attenuated virulence of the ΔelrR strain in a mouse peritonitis model. Virulence of simple and double elrR and elrA deletion mutants also suggests a remaining ElrR-independent expression of elrA in vivo and additional virulence-related genes controlled by ElrR.
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http://dx.doi.org/10.1128/JB.00121-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3697541PMC
July 2013

Incongruence between the cps type 2 genotype and host-related phenotypes of an Enterococcus faecalis food isolate.

Int J Food Microbiol 2012 Aug 14;158(2):120-5. Epub 2012 Jul 14.

ITQB, UNL, Apartado 127, 2781-901 Oeiras, Portugal.

Enterococcus faecalis is a nosocomial opportunistic pathogen, but is also found in fermented food products where it plays a fundamental role in the fermentation process. Previously, we have described the non-starter E. faecalis cheese isolate QA29b as harboring virulence genes and proven to be virulent in Galleria mellonella virulence model. In this study, we further characterized this food strain concerning traits relevant for the host-pathogen relationship. QA29b was found to belong to sequence type (ST) 72, a common ST among food isolates, and thus we consider it as a good representative of food E. faecalis strains. It demonstrated high ability to form biofilms, to adhere to epithelial cells and was readily eliminated by J774.A1 macrophage cells. Despite carrying the cps locus associated with the capsular polysaccharide CPS 2 type, cps genes were not expressed, likely due to an IS6770 inserted in the cpsC-cpsK promoter region. This work constitutes the first study of traits important for interaction, colonization and infection in the host performed on a good representative of E. faecalis food isolates. Reported results stress the need for a reliable serotyping assay of E. faecalis, as cps genotyping may not be reliable. Overall, QA29b characterization shows that despite its virulence potential in an insect model, this food strain is readily eliminated by mammalian macrophages. Thus, fine tuned approaches combining cellular and mammalian models are needed to address and elucidate the multifactorial aspect of virulence potential associated with food isolates.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2012.07.006DOI Listing
August 2012

The PavA-like fibronectin-binding protein of Enterococcus faecalis, EfbA, is important for virulence in a mouse model of ascending urinary tract infection.

J Infect Dis 2012 Sep 10;206(6):952-60. Epub 2012 Jul 10.

Institute of Microbiology, Università Cattolica del Sacro Cuore, Largo F Vito, 1 00168 Rome, Italy.

Enterococcus faecalis is an established nosocomial pathogen, yet the pathogenesis of enterococcal infections, particularly of urinary tract infections (UTIs), remains to be fully elucidated. Fibronectin-binding proteins have been identified as potent adhesins in pathogenic Gram-positive cocci. Here, we characterized EfbA, which is encoded by the enterococcal orthologue of Streptococcus pneumoniae pavA. Similar to PavA, the anchorless EfbA protein was localized to the enterococcal cell outer surface and bound to immobilized human fibronectin. In addition to abrogated EfbA expression, deletion of the efbA gene eliminated EfbA from the cell surface and drastically reduced the enterococcal cell binding to immobilized fibronectin. The ΔefbA deletion mutant was highly attenuated vs wild-type in a murine ascending UTI model, consistent with an increased tropism for the kidney relative to the bladder. These results provide the first evidence that EfbA of E. faecalis plays a role in UTIs, probably contributing to the pathogenesis in this site.
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http://dx.doi.org/10.1093/infdis/jis440DOI Listing
September 2012

The PavA-like fibronectin-binding protein of Enterococcus faecalis, EfbA, is important for virulence in a mouse model of ascending urinary tract infection.

J Infect Dis 2012 Sep 10;206(6):952-60. Epub 2012 Jul 10.

Institute of Microbiology, Università Cattolica del Sacro Cuore, Largo F Vito, 1 00168 Rome, Italy.

Enterococcus faecalis is an established nosocomial pathogen, yet the pathogenesis of enterococcal infections, particularly of urinary tract infections (UTIs), remains to be fully elucidated. Fibronectin-binding proteins have been identified as potent adhesins in pathogenic Gram-positive cocci. Here, we characterized EfbA, which is encoded by the enterococcal orthologue of Streptococcus pneumoniae pavA. Similar to PavA, the anchorless EfbA protein was localized to the enterococcal cell outer surface and bound to immobilized human fibronectin. In addition to abrogated EfbA expression, deletion of the efbA gene eliminated EfbA from the cell surface and drastically reduced the enterococcal cell binding to immobilized fibronectin. The ΔefbA deletion mutant was highly attenuated vs wild-type in a murine ascending UTI model, consistent with an increased tropism for the kidney relative to the bladder. These results provide the first evidence that EfbA of E. faecalis plays a role in UTIs, probably contributing to the pathogenesis in this site.
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http://dx.doi.org/10.1093/infdis/jis440DOI Listing
September 2012

Prevalence and characterization of antibiotic resistant Enterococcus faecalis in French cheeses.

Food Microbiol 2012 Sep 28;31(2):191-8. Epub 2012 Mar 28.

Actilait, 419, route des champs laitiers, F-74 800 La Roche sur Foron, France.

Prevalence of enterococci and antibiotic resistance profiles of Enterococcus faecalis was analyzed in 126 French cheeses from retail stores. Forty-four percent of pasteurized or thermised-milk cheeses, and up to 92% of raw-milk cheeses contained detectable enterococci. A total of 337 antibiotic resistant enterococci were isolated in 29% and 60% of pasteurized-milk and raw-milk cheeses, respectively. E. faecalis was the predominant antibiotic resistant species recovered (81%), followed by Enterococcus faecium (13%), and Enterococcus durans (6%). The most prevalent antibiotic resistances were tetracycline (Tet) and minocycline (Min), followed by erythromycin (Ery), kanamycin (Kan) and chloramphenicol (Cm). The most common multiple antibiotic resistance phenotype was Cm Ery Kan Min Tet. The occurrence of antibiotic genes, as searched by PCR, was 100 % for aph3'IIIa, 96 % for ermB, 90 % for tetM and 80 % for catA in isolates resistant to Kan, Ery, Tet or Cm, respectively. MLST analysis of 30 multidrug resistant E. faecalis revealed that ST19, CC21, CC25 and CC55 isolates were the most common in cheeses. In conclusion, as in many other European countries, French cheeses do contain enterococci with multiple antibiotics resistances. However, low occurrence of high-level gentamicin resistant or sulfamethoxazole/trimethoprim-resistant enterococci and absence of vancomycin- or ampicillin- resistant enterococci indicate that cheeses cannot be considered as a major reservoir for nosocomial multi-drug resistant enterococci.
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http://dx.doi.org/10.1016/j.fm.2012.03.009DOI Listing
September 2012

Large-scale screening of a targeted Enterococcus faecalis mutant library identifies envelope fitness factors.

PLoS One 2011 15;6(12):e29023. Epub 2011 Dec 15.

INRA, UMR1319 Micalis, Jouy-en-Josas, France.

Spread of antibiotic resistance among bacteria responsible for nosocomial and community-acquired infections urges for novel therapeutic or prophylactic targets and for innovative pathogen-specific antibacterial compounds. Major challenges are posed by opportunistic pathogens belonging to the low GC% gram-positive bacteria. Among those, Enterococcus faecalis is a leading cause of hospital-acquired infections associated with life-threatening issues and increased hospital costs. To better understand the molecular properties of enterococci that may be required for virulence, and that may explain the emergence of these bacteria in nosocomial infections, we performed the first large-scale functional analysis of E. faecalis V583, the first vancomycin-resistant isolate from a human bloodstream infection. E. faecalis V583 is within the high-risk clonal complex 2 group, which comprises mostly isolates derived from hospital infections worldwide. We conducted broad-range screenings of candidate genes likely involved in host adaptation (e.g., colonization and/or virulence). For this purpose, a library was constructed of targeted insertion mutations in 177 genes encoding putative surface or stress-response factors. Individual mutants were subsequently tested for their i) resistance to oxidative stress, ii) antibiotic resistance, iii) resistance to opsonophagocytosis, iv) adherence to the human colon carcinoma Caco-2 epithelial cells and v) virulence in a surrogate insect model. Our results identified a number of factors that are involved in the interaction between enterococci and their host environments. Their predicted functions highlight the importance of cell envelope glycopolymers in E. faecalis host adaptation. This study provides a valuable genetic database for understanding the steps leading E. faecalis to opportunistic virulence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029023PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3240637PMC
August 2012

The prolipoprotein diacylglyceryl transferase (Lgt) of Enterococcus faecalis contributes to virulence.

Microbiology (Reading) 2012 Mar 1;158(Pt 3):816-825. Epub 2011 Dec 1.

USC INRA 2017, Microbiologie de l'Environnement, EA956, Université de Caen, France.

Enterococcus faecalis is an opportunistic pathogen responsible for nosocomial infections. Lipoproteins in Gram-positive bacteria are translocated across the plasma membrane and anchored by the fatty acid group. They perform critical roles, with some described as virulence determinants. The aim of this study was to explore the roles of E. faecalis lipoproteins in the stress response and virulence. We constructed a mutant affected in the predicted prolipoprotein diacylglyceryl transferase gene lgt, and examined the role of Lgt in membrane anchoring, growth, the stress response and virulence. Inactivation of lgt enhanced growth in a high concentration of Mn(2+) or under oxidative stress in vitro, and significantly decreased virulence.
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http://dx.doi.org/10.1099/mic.0.055319-0DOI Listing
March 2012
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