scholarly journals Observations on the Role of TcdE Isoforms in Clostridium difficile Toxin Secretion

2015 ◽  
Vol 197 (15) ◽  
pp. 2600-2609 ◽  
Author(s):  
Revathi Govind ◽  
Leah Fitzwater ◽  
Rebekah Nichols
Keyword(s):  
Amino Acids ◽  
Clostridium Difficile ◽  
Cell Viability ◽  
Virulence Factors ◽  
Start Codon ◽  
Nosocomial Pathogen ◽  
Content Type ◽  
Antibiotic Associated Diarrhea ◽  
Toxin Secretion

ABSTRACTClostridium difficileis a major nosocomial pathogen and the principal causative agent of antibiotic-associated diarrhea. The toxigenicC. difficilestrains that cause disease secrete virulence factors, toxin A and toxin B, that cause colonic injury and inflammation.C. difficiletoxins have no export signature and are secreted by an unusual mechanism that involves TcdE, a holin-like protein. We isolated a TcdE mutant of the epidemic R20291 strain with impaired toxin secretion, which was restored by complementation with functional TcdE. In the TcdE open reading frame (ORF), we identified three possible translation start sites; each translated isoform may play a specific role in TcdE-controlled toxin release. We created plasmid constructs that express only one of the three TcdE isoforms and complemented the TcdE mutant with these isoforms. Western blot analysis of the complemented strains demonstrated that TcdE is translated efficiently from the start codon at the 25th and 27th positions in the predicted ORF, producing proteins with 142 amino acids (TcdE142) and 140 amino acids (TcdE140), respectively. TcdE166was not detected when expressed from its own ribosomal binding site (RBS). The effects of all three TcdE isoforms onC. difficilecell viability and toxin release were determined. Among the three isoforms, overexpression of TcdE166and TcdE142had a profound effect on cell viability compared to the TcdE140isoform. Similarly, TcdE166and TcdE142facilitated toxin release more efficiently than did TcdE140. The importance of these variations among TcdE isoforms and their role in toxin release are discussed.IMPORTANCEC. difficileis a nosocomial pathogen that has become the most prevalent cause of antibiotic-associated diarrhea in North America and in several countries in Europe. Most strains ofC. difficileproduce two high-molecular-weight toxins that are regarded as the primary virulence factors. The mechanism by which these large toxins are secreted from bacterial cells is not yet clear but involves TcdE, a holin-like protein. In this work, we show that TcdE could be translated from three different start codons, resulting in the production of three TcdE isoforms. Furthermore, we investigated the role of these isoforms in toxin release and cell lysis inC. difficile. An understanding of TcdE-dependent toxin secretion may be helpful for the development of strategies for preventing and treatingC. difficileinfections.

scholarly journals Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections

mBio ◽  
2015 ◽  
Vol 6 (3) ◽  
Author(s):  
Glen P. Carter ◽  
Anjana Chakravorty ◽  
Tu Anh Pham Nguyen ◽  
Steven Mileto ◽  
Fernanda Schreiber ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Animal Models ◽  
Virulence Factors ◽  
Host Response ◽  
Organ Damage ◽  
Intestinal Damage ◽  
Content Type ◽  
Animal Infection ◽  
Antibiotic Associated Diarrhea ◽  
First Time

ABSTRACTClostridium difficileis a leading cause of antibiotic-associated diarrhea, a significant animal pathogen, and a worldwide public health burden. Most disease-causing strains secrete two exotoxins, TcdA and TcdB, which are considered to be the primary virulence factors. Understanding the role that these toxins play in disease is essential for the rational design of urgently needed new therapeutics. However, their relative contributions to disease remain contentious. Using three different animal models, we show that TcdA+TcdB−mutants are attenuated in virulence in comparison to the wild-type (TcdA+TcdB+) strain, whereas TcdA−TcdB+mutants are fully virulent. We also show for the first time that TcdB alone is associated with both severe localized intestinal damage and systemic organ damage, suggesting that this toxin might be responsible for the onset of multiple organ dysfunction syndrome (MODS), a poorly characterized but often fatal complication ofC. difficileinfection (CDI). Finally, we show that TcdB is the primary factor responsible for inducing thein vivohost innate immune and inflammatory responses. Surprisingly, the animal infection model used was found to profoundly influence disease outcomes, a finding which has important ramifications for the validation of new therapeutics and future disease pathogenesis studies. Overall, our results show unequivocally that TcdB is the major virulence factor ofC. difficileand provide new insights into the host response toC. difficileduring infection. The results also highlight the critical nature of using appropriate and, when possible, multiple animal infection models when studying bacterial virulence mechanisms.IMPORTANCEClostridium difficileis a leading cause of antibiotic-associated diarrhea and an important hospital pathogen. TcdA and TcdB are thought to be the primary virulence factors responsible for disease symptoms ofC. difficileinfections (CDI). However, the individual contributions of these toxins to disease remain contentious. Using three different animal models of infection, we show for the first time that TcdB alone causes severe damage to the gut, as well as systemic organ damage, suggesting that this toxin might be responsible for MODS, a serious but poorly understood complication of CDI. These findings provide important new insights into the host response toC. difficileduring infection and should guide the rational development of urgently required nonantibiotic therapeutics for the treatment of CDI.

scholarly journals Mouse Relapse Model of Clostridium difficile Infection

2011 ◽  
Vol 79 (7) ◽  
pp. 2856-2864 ◽  
Author(s):  
Xingmin Sun ◽  
Haiying Wang ◽  
Yongrong Zhang ◽  
Kevin Chen ◽  
Barbara Davis ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Primary Infection ◽  
Recurrent Disease ◽  
Immunosuppressive Agents ◽  
Disease Recurrence ◽  
First Episode ◽  
Full Spectrum ◽  
Content Type ◽  
Antibiotic Associated Diarrhea

ABSTRACTClostridium difficileis the causative agent of primary and recurrent antibiotic-associated diarrhea and colitis in hospitalized patients. The disease is caused mainly by two exotoxins, TcdA and TcdB, produced by the bacteria. RecurrentC. difficileinfection (CDI) constitutes one of the most significant clinical issues of this disease, occurs in more than 20% of patients after the first episode, and may be increasing in frequency. However, there is no well-established animal model of CDI relapse currently available for studying disease pathogenesis, prevention, and therapy. Here we report the establishment of a conventional mouse model of recurrence/relapse CDI. We found that the primary episode of CDI induced little or no protective antibody response againstC. difficiletoxins and mice continued sheddingC. difficilespores. Antibiotic treatment of surviving mice induced a second episode of diarrhea, while a simultaneous reexposure of animals toC. difficilebacteria or spores elicited a full spectrum of CDI similar to that of the primary infection. Moreover, mice treated with immunosuppressive agents were prone to more severe and fulminant recurrent disease. Finally, utilizing this model, we demonstrated that vancomycin only delayed disease recurrence, whereas neutralizing polysera against both TcdA and TcdB completely protected mice against CDI relapse. In conclusion, we have established a mouse relapse CDI model that allows for future investigations of the role of the host immune response in the disease's pathogenesis and permits critical testing of new therapeutics targeting recurrent disease.

scholarly journals TheClostridium difficile spo0AGene Is a Persistence and Transmission Factor

2012 ◽  
Vol 80 (8) ◽  
pp. 2704-2711 ◽  
Author(s):  
Laura J. Deakin ◽  
Simon Clare ◽  
Robert P. Fagan ◽  
Lisa F. Dawson ◽  
Derek J. Pickard ◽  
...  
Keyword(s):  
Health Care ◽  
Clostridium Difficile ◽  
Murine Model ◽  
Persistent Infection ◽  
Transcriptional Regulator ◽  
Transmission Factor ◽  
Content Type ◽  
Antibiotic Associated Diarrhea ◽  
Significant Health

ABSTRACTClostridium difficileis a major cause of chronic antibiotic-associated diarrhea and a significant health care-associated pathogen that forms highly resistant and infectious spores. Spo0A is a highly conserved transcriptional regulator that plays a key role in initiating sporulation inBacillusandClostridiumspecies. Here, we use a murine model to study the role of theC. difficile spo0Agene during infection and transmission. We demonstrate thatC. difficile spo0Amutant derivatives can cause intestinal disease but are unable to persist within and effectively transmit between mice. Thus, theC. difficileSpo0A protein plays a key role in persistent infection, including recurrence and host-to-host transmission in mice.

scholarly journals Amino Acid Differences in the 1753-to-1851 Region of TcdB Influence Variations in TcdB1 and TcdB2 Cell Entry

mSphere ◽  
2017 ◽  
Vol 2 (4) ◽  
Author(s):  
Jonathan J. Hunt ◽  
Jason L. Larabee ◽  
Jimmy D. Ballard
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Clostridium Difficile ◽  
Cell Entry ◽  
Cell Binding ◽  
Content Type ◽  
Amino Acid Region ◽  
Antibiotic Associated Diarrhea ◽  
Insight Into ◽  
Acid Region

ABSTRACT TcdB is a major virulence factor produced by Clostridium difficile, a leading cause of antibiotic-associated diarrhea. Hypervirulent strains of C. difficile encode a variant of TcdB (TcdB2) that is more toxic than toxin derived from historical strains (TcdB1). Though TcdB1 and TcdB2 exhibit 92% overall identity, a 99-amino-acid region previously associated with cell entry and spanning amino acids 1753 to 1851 has only 77% sequence identity. Results from the present study indicate that the substantial sequence variation in this region could contribute to the differences in cell entry between TcdB1 and TcdB2 and possibly explain TcdB2’s heightened toxicity. Finally, during the course of these studies, an unusual aspect of TcdB cell entry was discovered wherein cell binding appeared to depend on endocytosis. These findings provide insight into TcdB’s variant forms and their mechanisms of cell entry. Clostridium difficile TcdB2 enters cells with a higher efficiency than TcdB1 and exhibits an overall higher level of toxicity. However, the TcdB2-specific sequences that account for more efficient cell entry have not been reported. In this study, we examined the contribution of carboxy-terminal sequence differences to TcdB activity by comparing the binding, uptake, and endosomal localization of TcdB1 and TcdB2 or selected recombinant fragments of these proteins. Our findings suggest that sequence differences in the amino acid 1753 to 1851 region proximal to the combined repetitive oligopeptide domain (CROP) support enhanced uptake of TcdB2 and localization of toxin in acidified endosomes. In the absence of this region, the CROP domains of both forms of the toxin exhibited similar levels of cell interaction, while the addition of amino acids 1753 to 1851 greatly increased toxin binding by only TcdB2. Moreover, the amino acid 1753 to 2366 fragment of TcdB2, but not TcdB1, accumulated to detectable levels in acidified endosomes. Unexpectedly, we discovered an unusual relationship between endocytosis and the efficiency of cell binding for TcdB1 and TcdB2 wherein inhibition of endocytosis by a chemical inhibitor or incubation at a low temperature resulted in a dramatic reduction in cell binding. These findings provide information on sequence variations that may contribute to differences in TcdB1 and TcdB2 toxicity and reveal a heretofore unknown connection between endocytosis and cell binding for this toxin. IMPORTANCE TcdB is a major virulence factor produced by Clostridium difficile, a leading cause of antibiotic-associated diarrhea. Hypervirulent strains of C. difficile encode a variant of TcdB (TcdB2) that is more toxic than toxin derived from historical strains (TcdB1). Though TcdB1 and TcdB2 exhibit 92% overall identity, a 99-amino-acid region previously associated with cell entry and spanning amino acids 1753 to 1851 has only 77% sequence identity. Results from the present study indicate that the substantial sequence variation in this region could contribute to the differences in cell entry between TcdB1 and TcdB2 and possibly explain TcdB2’s heightened toxicity. Finally, during the course of these studies, an unusual aspect of TcdB cell entry was discovered wherein cell binding appeared to depend on endocytosis. These findings provide insight into TcdB’s variant forms and their mechanisms of cell entry.

scholarly journals Cyclic Diguanylate Regulates Virulence Factor Genes via Multiple Riboswitches inClostridium difficile

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Robert W. McKee ◽  
Carissa K. Harvest ◽  
Rita Tamayo
Keyword(s):  
Gene Expression ◽  
Clostridium Difficile ◽  
Biofilm Formation ◽  
Toxin Production ◽  
Intestinal Colonization ◽  
Cyclic Diguanylate ◽  
Signaling Molecule ◽  
Content Type ◽  
Surface Motility

ABSTRACTThe intracellular signaling molecule cyclic diguanylate (c-di-GMP) regulates many processes in bacteria, with a central role in controlling the switch between motile and nonmotile lifestyles. Recent work has shown that inClostridium difficile(also calledClostridioides difficile), c-di-GMP regulates swimming and surface motility, biofilm formation, toxin production, and intestinal colonization. In this study, we determined the transcriptional regulon of c-di-GMP inC. difficile,employing overexpression of a diguanylate cyclase gene to artificially manipulate intracellular c-di-GMP. Consistent with prior work, c-di-GMP regulated the expression of genes involved in swimming and surface motility. c-di-GMP also affected the expression of multiple genes encoding cell envelope proteins, several of which affected biofilm formationin vitro. A substantial proportion of the c-di-GMP regulon appears to be controlled either directly or indirectly via riboswitches. We confirmed the functionality of 11 c-di-GMP riboswitches, demonstrating their effects on downstream gene expression independent of the upstream promoters. The class I riboswitches uniformly functioned as “off” switches in response to c-di-GMP, while class II riboswitches acted as “on” switches. Transcriptional analyses of genes 3′ of c-di-GMP riboswitches over a broad range of c-di-GMP levels showed that relatively modest changes in c-di-GMP levels are capable of altering gene transcription, with concomitant effects on microbial behavior. This work expands the known c-di-GMP signaling network inC. difficileand emphasizes the role of the riboswitches in controlling known and putative virulence factors inC. difficile.IMPORTANCEInClostridium difficile, the signaling molecule c-di-GMP regulates multiple processes affecting its ability to cause disease, including swimming and surface motility, biofilm formation, toxin production, and intestinal colonization. In this study, we used RNA-seq to define the transcriptional regulon of c-di-GMP inC. difficile. Many new targets of c-di-GMP regulation were identified, including multiple putative colonization factors. Transcriptional analyses revealed a prominent role for riboswitches in c-di-GMP signaling. Only a subset of the 16 previously predicted c-di-GMP riboswitches were functionalin vivoand displayed potential variability in their response kinetics to c-di-GMP. This work underscores the importance of studying c-di-GMP riboswitches in a relevant biological context and highlights the role of the riboswitches in controlling gene expression inC. difficile.

scholarly journals Germinant Synergy FacilitatesClostridium difficileSpore Germination under Physiological Conditions

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Travis J. Kochan ◽  
Michelle S. Shoshiev ◽  
Jessica L. Hastie ◽  
Madeline J. Somers ◽  
Yael M. Plotnick ◽  
...  
Keyword(s):  
Amino Acids ◽  
Clostridium Difficile ◽  
Spore Germination ◽  
Bile Salts ◽  
Gi Tract ◽  
Infectious Diarrhea ◽  
Content Type ◽  
Increased Risk ◽  
Calcium Reabsorption

ABSTRACTClostridium difficileis a Gram-positive obligate anaerobe that forms spores in order to survive for long periods in the unfavorable environment outside a host.C. difficileis the leading cause of nosocomial infectious diarrhea worldwide.C. difficileinfection (CDI) arises after a patient treated with broad-spectrum antibiotics ingests infectious spores. The first step inC. difficilepathogenesis is the metabolic reactivation of dormant spores within the gastrointestinal (GI) tract through a process known as germination. In this work, we aim to elucidate the specific conditions and the location within the GI tract that facilitate this process. Our data suggest thatC. difficilegermination occurs through a two-step biochemical process that is regulated by pH and bile salts, amino acids, and calcium present within the GI tract. Maximal germination occurs at a pH ranging from 6.5 to 8.5 in the terminal small intestine prior to bile salt and calcium reabsorption by the host. Germination can be initiated by lower concentrations of germinants when spores are incubated with a combination of bile salts, calcium, and amino acids, and this synergy is dependent on the availability of calcium. The synergy described here allows germination to proceed in the presence of inhibitory bile salts and at physiological concentrations of germinants, effectively decreasing the concentrations of nutrients required to initiate an essential step of pathogenesis.IMPORTANCEClostridium difficileis an anaerobic spore-forming human pathogen that is the leading cause of nosocomial infectious diarrhea worldwide. Germination of infectious spores is the first step in the development of aC. difficileinfection (CDI) after ingestion and passage through the stomach. This study investigates the specific conditions that facilitateC. difficilespore germination, including the following: location within the gastrointestinal (GI) tract, pH, temperature, and germinant concentration. The germinants that have been identified in culture include combinations of bile salts and amino acids or bile salts and calcium, butin vitro, these function at concentrations that far exceed normal physiological ranges normally found in the mammalian GI tract. In this work, we describe and quantify a previously unreported synergy observed when bile salts, calcium, and amino acids are added together. These germinant cocktails improve germination efficiency by decreasing the required concentrations of germinants to physiologically relevant levels. Combinations of multiple germinant types are also able to overcome the effects of inhibitory bile salts. In addition, we propose that the acidic conditions within the GI tract regulateC. difficilespore germination and could provide a biological explanation for why patients taking proton pump inhibitors are associated with increased risk of developing a CDI.

scholarly journals Role of Leptin-Mediated Colonic Inflammation in Defense against Clostridium difficile Colitis

2013 ◽  
Vol 82 (1) ◽  
pp. 341-349 ◽  
Author(s):  
Rajat Madan ◽  
Xiaoti Guo ◽  
Caitlin Naylor ◽  
Erica L. Buonomo ◽  
Donald Mackay ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Murine Model ◽  
Leptin Receptor ◽  
Mucosal Immune Response ◽  
Infectious Colitis ◽  
Content Type ◽  
Bacterial Peritonitis ◽  
Stat3 Signaling ◽  
Increased Risk

ABSTRACTThe role of leptin in the mucosal immune response toClostridium difficilecolitis, a leading cause of nosocomial infection, was studied in humans and in a murine model. Previously, a mutation in the receptor for leptin (LEPR) was shown to be associated with susceptibility to infectious colitis and liver abscess due toEntamoeba histolyticaas well as to bacterial peritonitis. Here we discovered that European Americans homozygous for the sameLEPRQ223R mutation (rs1137101), known to result in decreased STAT3 signaling, were at increased risk ofC. difficileinfection (odds ratio, 3.03;P= 0.015). The mechanism of increased susceptibility was studied in a murine model. Mice lacking a functional leptin receptor (db/db) had decreased clearance ofC. difficilefrom the gut lumen and diminished inflammation. Mutation of tyrosine 1138 in the intracellular domain of LepRb that mediates signaling through the STAT3/SOCS3 pathway also resulted in decreased mucosal chemokine and cell recruitment. Collectively, these data support a protective mucosal immune function for leptin inC. difficilecolitis partially mediated by a leptin-STAT3 inflammatory pathway that is defective in theLEPRQ223R mutation. Identification of the role of leptin in protection fromC. difficileoffers the potential for host-directed therapy and demonstrates a connection between metabolism and immunity.

scholarly journals Clostridium difficileLipoprotein GerS Is Required for Cortex Modification and Thus Spore Germination

mSphere ◽  
2018 ◽  
Vol 3 (3) ◽  
Author(s):  
Oscar R. Diaz ◽  
Cameron V. Sayer ◽  
David L. Popham ◽  
Aimee Shen
Keyword(s):  
Clostridium Difficile ◽  
Spore Germination ◽  
Protective Layer ◽  
Thick Layer ◽  
Lytic Enzyme ◽  
Gram Positive ◽  
Content Type ◽  
Clostridioides Difficile ◽  
Antibiotic Associated Diarrhea ◽  
Biochemical Analyses

ABSTRACTClostridium difficile, also known asClostridioides difficile, is a Gram-positive, spore-forming bacterium that is a leading cause of antibiotic-associated diarrhea.C. difficileinfections begin when its metabolically dormant spores germinate to form toxin-producing vegetative cells. Successful spore germination depends on the degradation of the cortex, a thick layer of modified peptidoglycan that maintains dormancy. Cortex degradation is mediated by the SleC cortex lytic enzyme, which is thought to recognize the cortex-specific modification muramic-δ-lactam.C. difficilecortex degradation also depends on thePeptostreptococcaceae-specific lipoprotein GerS for unknown reasons. In this study, we tested whether GerS regulates production of muramic-δ-lactam and thus controls the ability of SleC to recognize its cortex substrate. By comparing the muropeptide profiles of ΔgerSspores to those of spores lacking either CwlD or PdaA, both of which mediate cortex modification inBacillus subtilis, we determined thatC. difficileGerS, CwlD, and PdaA are all required to generate muramic-δ-lactam. Both GerS and CwlD were needed to cleave the peptide side chains from N-acetylmuramic acid, suggesting that these two factors act in concert. Consistent with this hypothesis, biochemical analyses revealed that GerS and CwlD directly interact and that CwlD modulates GerS incorporation into mature spores. Since ΔgerS, ΔcwlD, and ΔpdaAspores exhibited equivalent germination defects, our results indicate thatC. difficilespore germination depends on cortex-specific modifications, reveal GerS as a novel regulator of these processes, and highlight additional differences in the regulation of spore germination inC. difficilerelative toB. subtilisand other spore-forming organisms.IMPORTANCEThe Gram-positive, spore-forming bacteriumClostridium difficileis a leading cause of antibiotic-associated diarrhea. BecauseC. difficileis an obligate anaerobe, its aerotolerant spores are essential for transmitting disease, and their germination into toxin-producing cells is necessary for causing disease. Spore germination requires the removal of the cortex, a thick layer of modified peptidoglycan that maintains spore dormancy. Cortex degradation is mediated by the SleC hydrolase, which is thought to recognize cortex-specific modifications. Cortex degradation also requires the GerS lipoprotein for unknown reasons. In our study, we tested whether GerS is required to generate cortex-specific modifications by comparing the cortex composition of ΔgerSspores to the cortex composition of spores lacking two putative cortex-modifying enzymes, CwlD and PdaA. These analyses revealed that GerS, CwlD, and PdaA are all required to generate cortex-specific modifications. Since loss of these modifications in ΔgerS, ΔcwlD, and ΔpdaAmutants resulted in spore germination and heat resistance defects, the SleC cortex lytic enzyme depends on cortex-specific modifications to efficiently degrade this protective layer. Our results further indicate that GerS and CwlD are mutually required for removing peptide chains from spore peptidoglycan and revealed a novel interaction between these proteins. Thus, our findings provide new mechanistic insight intoC. difficilespore germination.

scholarly journals Clostridium difficile Toxins TcdA and TcdB Cause Colonic Tissue Damage by Distinct Mechanisms

2016 ◽  
Vol 84 (10) ◽  
pp. 2871-2877 ◽  
Author(s):  
Nicole M. Chumbler ◽  
Melissa A. Farrow ◽  
Lynne A. Lapierre ◽  
Jeffrey L. Franklin ◽  
D. Borden Lacy
Keyword(s):  
Clostridium Difficile ◽  
Apoptotic Cell ◽  
Large Body ◽  
Health Care Facilities ◽  
Dependent Manner ◽  
Content Type ◽  
Culture Model ◽  
Care Facilities ◽  
Antibiotic Associated Diarrhea ◽  
A Cell

As the major cause of antibiotic-associated diarrhea,Clostridium difficileis a serious problem in health care facilities worldwide.C. difficileproduces two large toxins, TcdA and TcdB, which are the primary virulence factors in disease. The respective functions of these toxins have been difficult to discern, in part because the cytotoxicity profiles for these toxins differ with concentration and cell type. The goal of this study was to develop a cell culture model that would allow a side-by-side mechanistic comparison of the toxins. Conditionally immortalized, young adult mouse colonic (YAMC) epithelial cells demonstrate an exquisite sensitivity to both toxins with phenotypes that agree with observations in tissue explants. TcdA intoxication results in an apoptotic cell death that is dependent on the glucosyltransferase activity of the toxin. In contrast, TcdB has a bimodal mechanism; it induces apoptosis in a glucosyltransferase-dependent manner at lower concentrations and glucosyltransferase-independent necrotic death at higher concentrations. The direct comparison of the responses to TcdA and TcdB in cells and colonic explants provides the opportunity to unify a large body of observations made by many independent investigators.

scholarly journals EfaR Is a Major Regulator of Enterococcus faecalis Manganese Transporters and Influences Processes Involved in Host Colonization and Infection

2013 ◽  
Vol 81 (3) ◽  
pp. 935-944 ◽  
Author(s):  
M. C. Abrantes ◽  
J. Kok ◽  
M. de F. Lopes
Keyword(s):  
Oxidative Stress ◽  
Metal Ions ◽  
Enterococcus Faecalis ◽  
Bacterial Endocarditis ◽  
Nosocomial Pathogen ◽  
Host Colonization ◽  
Content Type ◽  
Bacterial Pathogenicity

ABSTRACTMetal ions, in particular manganese, are important modulators of bacterial pathogenicity. However, little is known about the role of manganese-dependent proteins in the nosocomial pathogenEnterococcus faecalis, a major cause of bacterial endocarditis. The present study demonstrates that the DtxR/MntR family metalloregulator EfaR ofE. faecaliscontrols the expression of several of its regulon members in a manganese-dependent way. We also show thatefaRinactivation impairs the ability ofE. faecalisto form biofilms, to survive inside macrophages, and to tolerate oxidative stress. Our results reveal that EfaR is an important modulator ofE. faecalisvirulence and link manganese homeostasis to enterococcal pathogenicity.

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