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Staphylococcus lugdunensis is a coagulase-negative Staphylococcus that emerges as an important opportunistic pathogen. However, little is known about the regulation underlying the transition from commensal to virulent state. Based on knowledge of S. aureus virulence, we suspected that the agr quorum sensing system may be an important determinant for the pathogenicity of S. lugdunensis . We investigated the functions of the transcriptional regulator AgrA using the agrA deletion mutant. AgrA played a role in cell pigmentation: Δ argA mutant colonies were white while the parental strains were slightly yellow. Compared with the wild-type strain, the Δ argA mutant was affected in its ability to form biofilm and was less able to survive in mice macrophages. Moreover, the growth of Δ agrA was significantly reduced by the addition of 10% NaCl or 0.4 mM H 2 O 2 and its survival after 2 h in the presence of 1 mM H 2 O 2 was more than 10-fold reduced. To explore the mechanisms involved beyond these phenotypes, the Δ agrA proteome and transcriptome were characterized by mass spectrometry and RNA-Seq. We found that AgrA controlled several virulence factors as well as stress-response factors, which are well correlated with the reduced resistance of the Δ agrA mutant to osmotic and oxidative stresses. These results were not the consequence of the deregulation of RNAIII of the agr system, since no phenotype or alteration of the proteomic profile has been observed for the ΔRNAIII mutant. Altogether, our results highlighted that the AgrA regulator of S. lugdunensis played a key role in its ability to become pathogenic. IMPORTANCE Although belonging to the natural human skin flora, Staphylococcus lugdunensis is recognized as a particularly aggressive and destructive pathogen. This study aimed to characterize the role of the response regulator AgrA, which is a component of the quorum-sensing agr system and known to be a major element in the regulation of pathogenicity and biofilm formation in Staphylococcus aureus. In the present study, we showed that, contrary to S. aureus, the agrA deletion mutant produced less biofilm. Inactivation of agrA conferred a white colony phenotype and impacted S. lugdunensis in its ability to survive in mice macrophages and to cope with osmotic and oxidative stresses. By global proteomic and transcriptomic approaches, we identified the AgrA regulon, bringing molecular bases underlying the observed phenotypes. Together, our data showed the importance of AgrA in the opportunistic pathogenic behavior of S. lugdunensis allowing it to be considered as an interesting therapeutic target.

Background: Staphylococcus lugdunensis is a coagulase-negative Staphylococcus part of the commensal skin flora but emerge as an important opportunistic pathogen. Because iron limitation is a crucial stress during infectious process, we performed phenotypic study and compared proteomic profiles of this species incubated in absence and in presence of the iron chelator 2,2'-dipyridyl (DIP)., Results: No modification of cell morphology nor cell wall thickness were observed in presence of DIP. However iron-limitation condition promoted biofilm formation and reduced the ability to cope with oxidative stress (1 mM H 2 O 2 ). In addition, S. lugdunensis N920143 cultured with DIP was significantly less virulent in the larvae of Galleria mellonella model of infection than that grown under standard conditions. We verified that these phenotypes were due to an iron limitation by complementation experiments with FeSO 4 . By mass spectrometry after trypsin digestion, we characterized the first iron-limitation stress proteome in S. lugdunensis. Among 1426 proteins identified, 349 polypeptides were differentially expressed. 222 were more and 127 less abundant in S. lugdunensis incubated in iron-limitation condition, and by RT-qPCR, some of the corresponding genes have been shown to be transcriptionally regulated. Our data revealed that proteins involved in iron metabolism and carriers were over-expressed, as well as several ABC transporters and polypeptides linked to cell wall metabolism. Conversely, enzymes playing a role in the oxidative stress response (especially catalase) were repressed., Conclusions: This phenotypic and global proteomic study allowed characterization of the response of S. lugdunensis to iron-limitation. We showed that iron-limitation promoted biofilm formation, but decrease the oxidative stress resistance that may, at least in part, explained the reduced virulence of S. lugdunensis observed under low iron condition.

Staphylococcus lugdunensis is a commensal bacterium that can cause serious infection suggesting an ability to circumvent aspects of host immunity. We demonstrate here that macrophages fail to kill ingested S. lugdunensis and the bacteria persist for extended periods, without replicating, within mature LAMP-1-positive phagolysosomes. Phagocytosed S. lugdunensis also do not intoxicate host cells in contrast to Staphylococcus aureus. Optimal survival of S. lugdunensis requires O-acetylated peptidoglycan because an oatA mutant, which is more sensitive to killing by lysozyme than wild type, survived to a lesser extent in macrophages. In vitro models of macrophage infection reveal that viable intracellular S. lugdunensis bacteria can be made to grow by pharmacologic perturbation of phagosome function or by phagocyte intoxication by S. aureus toxins. Remarkably, replicating S. lugdunensis is not constrained by LAMP-1 and phosphatidylserine-positive endomembranes, which is distinct from S. aureus that replicates within phagolysosomes. In vivo, S. lugdunensis can also reside in the murine Kupffer cell where the bacteria persist without replicating and require oatA to resist killing in vivo. The intracellular environment of the macrophage represents a niche where S. lugdunensis can exist while protected from extracellular immune factors and may serve as a reservoir from which these bacteria could disseminate., (© 2018 John Wiley & Sons Ltd.)

We herein present the case of a 43-year-old male diabetic patient who presented with an aggressive form of infective endocarditis involving the tricuspid, mitral and aortic valves following a gluteal abscess due to infection with Staphylococcus lugdunensis. This coagulase-negative organism which is generally considered a component of the normal flora of the skin has however recently emerged as an unusually virulent pathogen responsible for both nosocomial and community-acquired infections. The case demonstrates the importance of paying utmost attention and ensuring a logical conclusion to the identification of persistent coagulase-negative blood cultures. In addition, it also shows the importance of early identification of this organism and aggressive antibiotic administration to avert endocarditis because of the unusual virulence of the organism. Staphylococcus lugdunensis is rarely a clinical specimen contaminant, and its isolation warrants further investigation and concerted treatment.

The implication of coagulase-negative staphylococci in human diseases is a major issue, particularly in hospital settings wherein these species often act as opportunistic pathogens. In addition, some coagulase-negative staphylococci such as S. lugdunensis have emerged as pathogenic bacteria, implicated in severe infections, particularly, osteoarticular infections, foreign-body-associated infections, bacteremia, and endocarditis. In vitro studies have shown the presence of several putative virulence factors such as adhesion factors, biofilm production, and proteolytic factors that might explain clinical manifestations. Taken together, the clinical and microbiological data might change the way clinicians and microbiologists look at S. lugdunensis in clinical samples., (Copyright © 2017 American Society for Microbiology.)

Objective: Staphylococcus lugdunensis is a coagulase-negative staphylococcus that displays an unusually high virulence rate close to that of Staphylococcus aureus. It also shares phenotypic properties with S. aureus and several studies found putative virulence factors. The objective of the study was to describe the clinical manifestations of S. lugdunensis infections and investigate putative virulence factors., Method: We conducted a prospective study from November 2013 to March 2016 at the University Hospital of Strasbourg. Putative virulence factors were investigated by clumping factor detection, screening for proteolytic activity, and sequence analysis using tandem nano-liquid chromatography-mass spectrometry., Results: In total, 347 positive samples for S. lugdunensis were collected, of which 129 (37.2%) were from confirmed cases of S. lugdunensis infection. Eighty-one of these 129 patients were included in the study. Bone and prosthetic joints (PJI) were the most frequent sites of infection (n=28; 34.6%) followed by skin and soft tissues (n=23; 28.4%). We identified and purified a novel protease secreted by 50 samples (61.7%), most frequently associated with samples from deep infections and PJI (pr 0.97 and pr 0.91, respectively). Protease peptide sequencing by nano-liquid chromatography-mass spectrometry revealed a novel protease bearing 62.42% identity with ShpI, a metalloprotease secreted by Staphylococcus hyicus., Conclusion: This study confirms the pathogenicity of S. lugdunensis, particularly in bone and PJI. We also identified a novel metalloprotease called lugdulysin that may contribute to virulence., (Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Coagulase negative staphylococci are normal inhabitant of the human skin flora that account for an increasing number of infections, particularly hospital-acquired infections. Staphylococcus lugdunensis has emerged as a most virulent species causing various infections with clinical characteristics close to what clinicians usually observe with Staphylococcus aureus and both bacteria share more than 70% of their genome. Virulence of S. aureus relies on a large repertoire of virulence factors, many of which are encoded on mobile genetic elements. S. lugdunensis also bears various putative virulence genes but only one complete genome with extensive analysis has been published with one prophage sequence (φSL2) and a unique plasmid was previously described. In this study, we performed de novo sequencing, whole genome assembly and annotation of seven strains of S. lugdunensis from VISLISI clinical trial. We searched for the presence of virulence genes and mobile genetics elements using bioinformatics tools. We identified four new prophages, named φSL2 to φSL4, belonging to the Siphoviridae class and five plasmids, named pVISLISI_1 to pVISLISI_5. Three plasmids are homologous to known plasmids that include, amongst others, one S. aureus plasmid. The two other plasmids were not described previously. This study provides a new context for the study of S. lugdunensis virulence suggesting the occurrence of several genetic recombination' with other staphylococci., (© The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Objectives: The aim of this study was to assess the characteristics of periprosthetic joint infection (PJI) due to Staphylococcus lugdunensis and to compare these to the characteristics of PJI due to Staphylococcus aureus and Staphylococcus epidermidis., Methods: A retrospective multicentre study including all consecutive cases of S. lugdunensis PJI (2000-2014) was performed. Eighty-eight cases of staphylococcal PJI were recorded: 28 due to S. lugdunensis, 30 to S. aureus, and 30 to S. epidermidis, as identified by Vitek 2 or API Staph (bioMérieux)., Results: Clinical symptoms were more often reported in the S. lugdunensis group, and the median delay between surgery and infection was shorter for the S. lugdunensis group than for the S. aureus and S. epidermidis groups. Regarding antibiotic susceptibility, the S. lugdunensis strains were susceptible to antibiotics and 61% of the patients could be treated with levofloxacin + rifampicin. The outcome of the PJI was favourable for 89% of patients with S. lugdunensis, 83% with S. aureus, and 97% with S. epidermidis., Conclusion: S. lugdunensis is an emerging pathogen with a pathogenicity quite similar to that of S. aureus. This coagulase-negative Staphylococcus must be identified precisely in PJI, in order to select the appropriate surgical treatment and antibiotics ., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Staphylococcus lugdunensis is a coagulase negative bacterial pathogen that is particularly associated with severe cases of infectious endocarditis. Unique amongst the coagulase-negative staphylococci, S. lugdunensis harbors an iron regulated surface determinant locus (isd). This locus facilitates the acquisition of heme as a source of nutrient iron during infection and allows iron limitation caused by "nutritional immunity" to be overcome. The isd locus is duplicated in S. lugdunensis HKU09-01 and we show here that the duplication is intrinsically unstable and undergoes accordion-like amplification and segregation leading to extensive isd copy number variation. Amplification of the locus increased the level of expression of Isd proteins and improved binding of hemoglobin to the cell surface of S. lugdunensis. Furthermore, Isd overexpression provided an advantage when strains were competing for a limited amount of hemoglobin as the sole source of iron. Gene duplications and amplifications (GDA) are events of fundamental importance for bacterial evolution and are frequently associated with antibiotic resistance in many species. As such, GDAs are regarded as evolutionary adaptions to novel selective pressures in hostile environments pointing towards a special importance of isd for S. lugdunensis. For the first time we show an example of a GDA that involves a virulence factor of a Gram-positive pathogen and link the GDA directly to a competitive advantage when the bacteria were struggling with selective pressures mimicking "nutritional immunity"., Competing Interests: The authors have declared that no competing interests exist.

Staphylococcus lugdunensis is a coagulase-negative staphylococcus of growing importance and atypical behavior. The infections caused by this microorganism are becoming more frequent, having a broader spectrum. Psoas abscesses caused by this germ are rare, with few cases reported in the literature. In this work, we present a case of a psoas abscess caused by S. lugdunensis in a patient suffering from diabetes mellitus and rheumatoid arthritis, which was treated with intravenous cloxacillin with a good outcome., (Copyright © 2016 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.)

This study was conducted to determine the frequency of Staphylococcus lugdunensis in different clinical samples. Out of 690 clinical samples, a total of 178 coagulase negative staphylococci (CoNS) isolates were recovered. CoNS were identified as 10 different species; 22 isolates belonged to Staphylococcus lugdunensis. Two specific genes for S. lugdunensis were used (tanA gene and fbl gene) to confirm identification. Both of these specific genes were detected in 15 (68.1%) of 22 isolates that were identified phenotypically. The results of oxacillin MIC showed that 7 of the 15 (46.6%) S. lugdunensis isolates were oxacillin resistant. The antibiotic susceptibility testing against 16 antibiotics showed that resistance rates were variable towards these antibiotics. Eight of fifteen S. lugdunensis isolates (53.3%) were β-lactamase producer. Results of molecular detection of mecA gene found that mecA gene was detected in 6 (40%) of 15 S. lugdunensis. All of these 6 isolates (S1, S2, S3, S4, S5, and S6) were resistant to oxacillin. One isolate (S7) was resistant to oxacillin but mecA was not detected in this isolate. This study is a first record of isolation and characterization of methicillin resistant S. lugdunensis (MRSL) from clinical samples in Iraq.

Staphylococcus lugdunensis is a commensal of humans and an opportunistic pathogen. It can cause an aggressive form of infective endocarditis in healthy humans akin to Staphylococcus aureus. Here we compared the virulence of the genome-sequenced S. lugdunensis strain N920143 to S. aureus in an experimental rat endocarditis model. N920143 caused a milder course of disease with lower levels of bacteraemia and smaller endocardial vegetations than S. aureus strain Newman. However, vegetations were comparable to those produced by S. aureus MRSA strain COL. Little is known about virulence factors of S. lugdunensis as systems to manipulate the bacterium genetically are currently limited. Here, we report a method for electroporation of S. lugdunensis with plasmid DNA and demonstrate that the low efficiency of transformation is due to the activity of a conserved type I restriction-modification system. To streamline the transformation process, we constructed SL01B, an E. coli strain expressing the hsdM/hsdS genes of N920143. Modified plasmid DNA isolated from SL01B transformed S. lugdunensis strains from clonal complexes 1 and 2 efficiently. A deletion mutant of N920143 lacking sortase A was significantly less virulent than the wild-type in the endocarditis model. Mutants defective in single surface proteins Fbl or vWbl were not significantly different from the wild-type but showed trends towards reduced virulence.

Background: Staphylococcus lugdunensis, a species of coagulase-negative staphylococci is associated with a wide variety of infections ranging from mild skin and soft tissue infections to serious infections which include brain abscess, chronic osteomyelitis and infective endocarditis. The aim of this study was to review cases of S. lugdunensis bacteraemia isolated from a New Zealand tertiary institution and describe the clinical presentation, diagnosis and treatment of the patients., Methods: All blood cultures reported positive for S. lugdunensis from the Microbiology Laboratory, Waikato Hospital, New Zealand between March 2006 to April 2011 were reviewed., Results: A total of 11 cases of S. lugdunensis bacteraemia were identified during the 5-year period. Three (27%) cases were due to infective endocarditis with one delayed diagnosis due to the failure of recognize the coagulase-negative Staphylococcus. Transthoracic or transoesophageal echocardiography was performed in 6 (55%) of the patients. One patient with endocarditis required early surgery and the other two were managed successfully with intravenous antibiotics. There was no in hospital mortality in the patients with endocarditis. The remaining 8 cases included 1 (9%) necrotizing fasciitis, 1 (9%) immunocompromised nosocomial multiple organism sepsis, 1 (9%) deep tissue infection requiring 6 weeks of intravenous antibiotics, 2 (18.5%) superficial skin infection, 1 (9%) nosocomial post-pacemaker insertion infection and 2 (18.5%) had fever of unknown origin. All isolates were sensitive to Flucloxacillin and Vancomycin. Overall the survival rate of the acute presentation and treatment was 91% (10/11)., Conclusion: Three of our 11 patients (27%) with S. lugdunensis bacteraemia were diagnosed with infective endocarditis. Evaluation for endocarditis is therefore advised in patients who have positive blood culture for this organism.

Background/purpose: Infective endocarditis caused by Staphylococcus lugdunensis is a rare disease. Since its first description in 1988, there have only been a few reports of this disease and the causative organism. These publications were primarily case reports and brief case series. We conducted a literature review to identify the nature of the disease and its risk factors., Methods: We retrospectively reviewed the cases reported between 1988 and 2008 by searching the relevant literature using the keywords "endocarditis" and "Staphylococcus lugdunensis" in the Medline database. All cases included met the definition of the modified Duke criteria., Results: For the period 1988-2008, 67 cases from 27 articles were reviewed. The mean age of individuals was 53.9 years. Left-sided valvular endocarditis represented 52 (82.5%) of cases and native-valve endocarditis was evident in 48 (78.7%) of cases. A large proportion (82%) of 50 S. lugdunensis strains were susceptible to penicillin. Valve replacement operations were performed in 42 (66.7%) patients and the mortality rate was 38.8%. Univariate analysis showed a higher mortality rate in patients aged more than 50 years, those treated before 1995, those treated with antibiotics alone, and those with growth not detected by echocardiography. Medical treatment alone was the independent risk factor for mortality by multivariate analysis., Conclusion: S. lugdunensis endocarditis led to substantial morbidity and mortality. Detailed microbiological identification, echocardiography evaluation, and valve replacement may improve the clinical outcome of individuals with S. lugdunensis endocarditis., (Copyright © 2010 Taiwan Society of Microbiology. Published by Elsevier B.V. All rights reserved.)

Staphylococcus Lugdunensis is a rare but potentially aggressive pathogen in the family of coagulase negative staphylococcus (CoNS). It can cause a wide variety of infections ranging from superficial skin to fulminant infections like endocarditis. Both native and prosthetic valve endocarditis due to S. lugdunensis have been documented in the English literature. Eight cases of pacemaker lead endocarditis due to S. lugdunensis have been described so far. We present the ninth case of pacemaker lead and first case of automatic implantable cardioverter defibrillator (AICD) lead endocarditis due to S. lugdunensis., (Copyright © 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)