Article:Staphylococcus aureus Toxins and Diabetic Foot Ulcers: Role in Pathogenesis and Interest in Diagnosis (4963842)

From ScienceSource
Jump to: navigation, search

This page is the ScienceSource HTML version of the scholarly article described at https://www.wikidata.org/wiki/Q26741281. Its title is Staphylococcus aureus Toxins and Diabetic Foot Ulcers: Role in Pathogenesis and Interest in Diagnosis and the publication date was 2016-07-07. The initial author is Catherine Dunyach-Remy.

Fuller metadata can be found in the Wikidata link, which lists all authors, and may have detailed items for some or all of them. There is further information on the article in the footer below. This page is a reference version, and is protected against editing.



Converted JATS paper:

Journal Information

Title: Toxins

Staphylococcus aureus Toxins and Diabetic Foot Ulcers: Role in Pathogenesis and Interest in Diagnosis

  • Catherine Dunyach-Remy
  • Christelle Ngba Essebe
  • Albert Sotto
  • Jean-Philippe Lavigne
  • Vernon L. Tesh (Academic Editor)

1Institut National de la Santé Et de la Recherche Médicale U1047, Université de Montpellier, UFR de Médecine, Nîmes 30908, France; catherine.remy@chu-nimes.fr (C.D.-R.); ngbachristelle@hotmail.fr (C.N.E.); albert.sotto@chu-nimes.fr (A.S.)

2Service de Microbiologie, Centre Hospitalo-Universitaire Carémeau, Nîmes 30029, France

3Service des Maladies Infectieuses et Tropicales, Centre Hospitalo-Universitaire Carémeau, Nîmes 30029, France

Publication date (epub): 7/2016

Publication date (collection): 7/2016

Abstract

Infection of foot ulcers is a common, often severe and costly complication in diabetes. Diabetic foot infections (DFI) are mainly polymicrobial, and Staphylococcus aureus is the most frequent pathogen isolated. The numerous virulence factors and toxins produced by S. aureus during an infection are well characterized. However, some particular features could be observed in DFI. The aim of this review is to describe the role of S. aureus in DFI and the implication of its toxins in the establishment of the infection. Studies on this issue have helped to distinguish two S. aureus populations in DFI: toxinogenic S. aureus strains (harboring exfoliatin-, EDIN-, PVL- or TSST-encoding genes) and non-toxinogenic strains. Toxinogenic strains are often present in infections with a more severe grade and systemic impact, whereas non-toxinogenic strains seem to remain localized in deep structures and bone involving diabetic foot osteomyelitis. Testing the virulence profile of bacteria seems to be a promising way to predict the behavior of S. aureus in the chronic wounds.

Paper

1. Introduction

Foot ulcers are common in diabetic patients. Its prevalence varies between 15% and 25% [[1]]. Infection of these ulcers is a frequent (40%–80%) complication representing a major cause of mortality and morbidity [[2]]. It is estimated to be the most common reason of lower-limb amputations [[3],[4],[5]]. The pathophysiology of diabetic foot infection (DFI) is quite complex. The prevalence and severity are a consequence of host-related processes (e.g., immunopathy, neuropathy and arteriopathy) and pathogen-related factors (e.g., virulence, antibiotic-resistance and microbial organization) (Figure 1) [[6],[7],[8]].

DFI pose many problems in clinical practice in terms of both management and diagnosis [[9]]. Indeed, the presence of impaired leukocyte functions and/or peripheral arterial disease may reduce the local inflammatory response and classical signs or symptoms of local infection [[10],[11]]. Moreover, systemic signs of toxicity (e.g., leukocytosis or fever) may be lacking or appear late, even in severe cases [[12],[13],[14]]. Microbiological diagnosis of these DFI also encounters many limitations. As microorganisms colonize all chronic wounds, the diagnosis of DFI should not be based only on the microbiological analysis of a wound culture, but also on clinical findings [[5],[9],[15]]. The Infectious Diseases Society of America (IDSA) and the International Working Group on the Diabetic Foot (IWGDF) have developed clinical criteria for classifying the severity of DFI (Table 1) [[15],[16]].

For many decades, culturing wound specimens were the only way to determine the causative pathogen(s) in a DFI. As microorganisms are always present on every skin wound and the DFI are often polymicrobial, the variability of bacterial virulence factors and the level of host resistance must also be taken into account. In fact, the different organisms isolated from infected wounds do not have a similar pathogenic impact, and evaluation of the intrinsic virulence potential of isolated bacteria to identify their real pathogenicity seems a promising way to best characterize the infection and to distinguish infection from colonization [[16]].

Several studies have shown that DFI are polymicrobial, and Staphylococcus aureus is the pathogen most frequently isolated [[17],[18],[19],[20],[21],[22]]. S. aureus is both a commensal bacterium and a human pathogen. Indeed, approximately 30% of the human population is colonized with S. aureus [[23]]. Importantly, this bacterium causes a wide range of clinical infections (e.g., bacteremia, endocarditis, skin and soft tissue, osteoarticular, pulmonary and device-related infections) [[24]]. The numerous virulence factors and toxins produced by S. aureus during infection are well characterized [[22]]. However, some specific features could be observed in DFI. The aim of this review is to describe the role of S. aureus in DFI and the implication of its toxins in the establishment of the infection.

2. DFI and Staphylococcus aureus

2.1. Clinical Aspects of DFI

Many DFIs are superficial at presentation. However, bacteria can spread to subcutaneous tissues, including tendons, joints, fascia, muscle and bone. DFIs were classified by their clinical severity, ranging from mild (~35% of cases, depending on site of presentation), through moderate (~30%–60%), to severe (~5%–25%) [[25]]. The IWGDF and the IDSA have proposed simple clinical criteria for classifying the infection of diabetic foot ulcer (DFU) based on classical signs and symptoms of inflammation (Table 1) [[3],[15],[25],[26],[27]]. This scheme helps to predict whether hospitalization would be required and the clinical outcome. Moreover, various factors have been suggested as markers of DFI when classical signs are not obvious. These include the identification of friable or discolored granulation tissue, necrosis, fetid odor, non-purulent secretions, delay in healing despite otherwise adequate ulcer management and the discovery of unexplained hyperglycemia [[16],[25]]. Interestingly, neither toxic shock syndrome nor toxinogenic manifestations could be clearly diagnosed in DFI.

2.2. Osteomyelitis

Infection of bone, or osteomyelitis, is found in ~50%–60% of patients hospitalized for a DFI and ~10%–20% of apparently less severe infections presenting in the ambulatory setting [[28]]. Bone infection results in inflammatory destruction, bone necrosis and new bone formation. It typically involves the forefoot and develops by contiguous spread from overlying soft tissue, penetration through the cortical bone and into the medullary cavity. The clinical presentation of diabetic foot osteomyelitis (DFOM) can vary with the site, the presence of any associated abscess or soft tissue involvement, the extent of bone infection, the bacterial species and the adequacy of limb perfusion. Osteomyelitis is frequently associated with vascular insufficiency [[24],[28],[29]].

Two clinical manifestations are frequently found during DFOM: an ulcer lying over a bony prominence (particularly when it fails to heal despite adequate off-loading) and a ‘sausage toe’. Osteomyelitis can, however, occur in the absence of overlying local signs of inflammation [[30]].

2.3. Matrix Metalloproteinases and DFI

During DFI, wound healing is hampered by mechanisms including a low growth factor activity, a reduced cellular proliferation, an elevated inflammatory markers and high levels of proteases [[31]].

The proteases are enzymes that act to control the degradation of extracellular matrix (ECM) [[32]]. The major group of proteases involved in the wound healing process are the matrix metalloproteinases (MMP) (e.g., MMP-2, MMP-8, MMP-9 and the serine proteases (human neutrophil elastase, HNE)). MMPs are endopeptidases whose physiological functions are to degrade the different components of the cutaneous tissue (collagen type I, elastin, etc.) and to facilitate keratinocyte migration and re-epithelialization [[33],[34]]. HNE is an enzyme acting on a wide range of proteins in the ECM and on inflammatory mediators [[31]]. The MMPs’ activity is inhibited by tissue inhibitors of metalloproteinases (TIMPs) [[35]]. The balance between the level of proteases and their inhibitors is essential to allow a physiological healing process [[36]].

In DFI, under the hypoxic and inflammatory environment, the presence of elevated levels of MMPs could be noted as opposed to decreased levels of TIMPs [[36],[37],[38],[39]]. This elevated protease activity participates in the important destruction of the ulcer ECM. It impairs the release of the different factors regulating the wound healing process (the collagen synthesis is deregulated; the growth factor synthesis and action are stopped) and affects extracellular matrix components, such as fibronectin [[40]]. All of these elements stall the wound in a chronic inflammatory phase without progressing to healing. However, no clear link between delayed healing and elevated protease activity has been described. This reinforces the need to understand the organization/cooperation between bacteria species that can modulate local inflammation and host MPP production.

In addition to human MMPs, some bacteria produce proteases that have a role in the healing of infected wounds. For example, the zinc-metalloproteinase, elastase, produced by Pseudomonas aeruginosa, induces degradation of fibroblast proteins and proteoglycans in chronic wounds and has also been shown to degrade host immune cell mediators. The microbial proteases participate also in the degradation of human ulcer fluid and inhibit fibroblast growth. It has now been suggested that human and bacterial MMPs act synergistically to maintain the lesion in a chronicity status [[32]]. Many pathogenic bacteria isolated on wounds (including S. aureus) are able to produce metalloproteinases.

2.4. Prevalence of S. aureus in DFIs

In Occidental countries, Gram-positive aerobic cocci are the main microorganisms responsible for DFI with S. aureus the most commonly isolated bacteria, alone or in combination, in superficial or deep infection (Figure 2) [[19],[20],[29],[30],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72]]. In warmer countries (particularly in Asia and Africa), Gram-negative bacilli are more prevalent.

Many cases of deep infections and DFOM are polymicrobial. Also in this case, S. aureus is the main isolated bacteria, present in 30%–60% of cases [[25]].

2.5. Resistance of S. aureus in DFIs

The prevalence of methicillin-resistant S. aureus (MRSA) in DFI varies among countries with an exacerbation in countries that are less developed (Figure 2) [[19],[20],[28],[29],[30],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73]]. MRSA are more often isolated from patients who have been previously hospitalized or reside in a chronic care facility, who have recently received antibiotic therapy or who have had a previous amputation [[41],[74]].

In France, the prevalence of MRSA increased since the late 1990s [[73],[75]]. Around 2005, different protocols were developed. National guidelines were implemented for the better management of DFI, notably concerning the debridement procedures, the microbiological samplings and antibiotic use [[76]]. The results of these guidelines entailed a significant decrease in the number of bacteria isolated per sample, in the increased rate of Gram-positive cocci and in the prevalence rate of multidrug-resistant bacteria, notably MRSA [[3],[15],[28],[77]]. Concomitantly, hospital infection control measures have been improved [[42],[78],[79]], notably on the use of hydro-alcoholic solution for handwashing [[80]]. These measures have been associated with a reduction in MRSA diffusion [[41]].

For some authors, the isolation of MRSA in DFIs would be associated with more severe infections. However, different articles showed a similar clinical presentation and outcomes between MRSA and other pathogens [[81],[82],[83]].

Finally, some cases of DFIs due to vancomycin-resistant S. aureus have been described [[84],[85]]. This type of resistance remains uncommon.

2.6. Pathogenesis

The pathogenesis of S. aureus in DFI is classical and corresponds to the physiopathology of skin and soft tissue infection (SSTI) [[24],[86]]. The first defense against S. aureus infection is the neutrophil response. When S. aureus enters the injured skin, neutrophils and macrophages migrate to the site of infection. S. aureus evades this response using different methods (e.g., blocking sequestering host antibodies, chemotaxis of leukocytes, hiding from detection via capsule or biofilm formation and resisting destruction after ingestion by phagocytes).

The knowledge of S. aureus pathogenicity reveals that these bacteria seem to be adapted for soft tissue and bone infections. Indeed the majority of infections remain localized to the feet. Generally, systemic infection secondary to diabetic foot is less prevalent (around 10%). This becomes particularly noticeable when analyzing the infection process [[87]]. The first event at the beginning of DFI is the adhesion to surface components (fibrinogen, fibronectin and epidermal keratinocytes). S. aureus attachment to ulcer surface depends on bacterial expression of numerous surface proteins that mediate adherence to components of bone matrix and collagen [[88]]. These bacterial cell surface receptors correspond to adhesins or microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) [[89],[90],[91],[92]] (Figure 3). MSCRAMMs facilitate bacterial adhesion to skin tissue. Moreover adhesins are essential in intracellular bone invasion. Indeed, S. aureus can invade osteoblasts [[93]], fibroblasts and endothelial cells. In the intracellular compartment this bacterium forms small-colony variants (SCVs) [[94]]. Thus, they are able to survive in a metabolically inactive state while preserving the integrity of the host cell. SCVs possess important metabolic and phenotypic differences from ordinary S. aureus isolates [[94],[95],[96]]. Indeed, they are relatively resistant to antibiotics [[97],[98]] and, hence, difficult to eradicate with antibiotic therapy [[99]].

Moreover, the synthesis and secretion of glycocalyx play a role in the virulence of S. aureus. This is also documented for strains obtained from DFI [[100]]. The polysaccharide production begins immediately after the adhesion and covers the bacteria, representing an essential component for the development of a ‘biofilm’ (Figure 3) [[101],[102],[103],[104]].

In addition to specific adherence mechanisms, S. aureus have a number of other virulence factors involved in the infection of soft tissues and bones. S. aureus is able to secrete toxins, which can lead to tissue necrosis (Figure 3). Toxins produced by S. aureus have an important role in the deepening and spread of the infection in the patient with DFI.

3. Staphylococcus aureus Toxins in DFIs

The ability of S. aureus to cause DFI is defined by numerous virulence factors among which secreted toxins play an important role (participation in colonization, persistence, evasion of the immune system and dissemination) [[105]]. These toxins include: the pore-forming toxins, the exfoliatins, the superantigen exotoxins (SAg) and the EDIN (epidermal cell differentiation inhibitors) toxins. These cytolytic toxins can damage membranes of host cells leading to cell lysis [[106]]. Hemolysins lyse red blood cells, while leukotoxins target white blood cells.

3.1. Pore-Forming Toxins

Pore-forming toxins (PFT) of S. aureus, through pore-forming and pro-inflammatory activities, have the ability to lyse host cells. They include the single-component α-toxin (or α-hemolysin), the phenol-soluble modulins (PSMs) and bi-component leukotoxins, including Panton-Valentine leukocidin (PVL), γ-hemolysin and leukocidin D/E [[86]].

3.1.1. α-Toxin

This PFT is a beta-barrel forming toxin, which consists of beta sheets [[107]]. It is released by the majority of S. aureus as a water-soluble monomer [[108]]. Its targets are red blood cells and leukocytes except neutrophils [[109]]. Although α-toxin is the most frequently secreted, few studies have focused on the role of this hemolysin produced by S. aureus in DFI. In a French national study, almost all of the strains harbored the α-toxin-encoding gene hla independently of the grade [[110]]. However, this proportion varies between methicillin-susceptible S. aureus (MSSA) and MRSA. The α-hemolysin gene was significantly less present in MRSA (16.4%) than in MSSA strains (100%) [[48]]. As we noted previously, DFIs caused by MRSA present a similar severity of infections to MSSA, excluding an increased role of α-toxin in the pathogenicity of MSSA.

3.1.2. Phenol Soluble Modulins

Recently, the role of a family of secreted peptides, the phenol-soluble modulins (PSMs), has been described in staphylococcal pathogenesis [[111]]. PSMs are produced by the majority of S. aureus strains [[112]]. These toxins are membrane-injuring toxins. They are structurally characterized as a family of seven small amphipathic α-helical peptides. Some PSMs are described: PSMα1–PSMα4 and delta-toxin. Like LukAB (described below), they induce human neutrophil lysis after phagocytosis, a pathogenesis mechanism of great importance for the high toxicity [[113],[114]]. In DFI, to date, no report has evaluated the significance of these virulence factors in the pathogenicity of S. aureus.

3.1.3. The Bi-Component Leukotoxins

S. aureus produces some bi-component toxins structurally similar to α-toxin. These toxins result from the association of the class S (Slow) component and the class F (Fast) component based on their electrophoretic mobility [[105]]. They induce the activation and the permeability of the target cells. They can lyse phagocytes (monocytes-macrophages and neutrophils), which is considered important for S. aureus immune evasion [[115],[116]]. These PFTs include: (i) the gamma-toxin (gamma-hemolysins HlgA and HlgC/HlgB); (ii) the Panton-Valentine leukocidin (PVL) [[117]], corresponding to the LukS-PV and LukF-PV proteins; (iii) the leukocidins LukDE [[118],[119]]; and LukAB [[116]] (also known as LukGH) [[116]].

The hlg gene cluster encoding for hemolysin-γ (Hlg) and hemolysin-γ2 (Hlg2) is located in the core genome. This cluster is present in almost all S. aureus strains. These toxins play a role in septic arthritis and could help community-acquired MRSA (CA-MRSA) to survive in human blood during infection [[120],[121]]. In DFI, all of the isolated strains possess the different components of the hlg gene [[48],[110]]. Interestingly, a variant of hlg (hlgv) is significantly associated with strains isolated from infected ulcers (Grades 2–4) [[110],[122]].

The most well-known leukotoxin is PVL. PVL confers cytotoxicity on neutrophils and monocytes-macrophages, leading to a high virulence [[123]]. LukS-/LukF-PV are encoded within lysogenic phages [[124],[125]]. Several lukS-/lukF-PV-transducing phages have been discovered [[105]]. This particular genetic organization involves an easy horizontal transmission of PVL genes in Staphylococcus spp. [[126]].

The PVL-positive strains are responsible for SSTIs (abscesses, furuncles, carbuncles or necrotizing fasciitis), severe necrotizing pneumonia and aggressive bone and joint infections [[48],[105],[127],[128]]. However their prevalence is extremely diverse, varying between less than 5% and 67% of MSSA [[129],[130],[131],[132],[133],[134],[135],[136]]. Interestingly, PVL-positive strains are statistically associated with younger patients [[137]]. This toxin has been linked to CA-MRSA infections [[129]], even if some CA-MRSA isolates do not carry the lukS/lukF-PV genes [[138]]. A high prevalence of CA-MRSA was observed in Africa [[139]], the Middle East [[140],[141]], Asia [[142]] and America [[143]].

The PVL-producing clones were rarely isolated from DFI (Table 2) [[48],[110],[122],[144],[145]]. However, this prevalence varies between countries: France (~3%), Algeria and The Netherlands (~14%) [[48],[146]]. The main PVL-producing strains isolated from DFI belong to ST80-MRSA (14/21 strains), followed by ST152 (6/21) and CC30 (1/21). ST80 is the main PVL clone circulating in Europe and North Africa [[147],[148],[149]]. Rates of PVL-producing clones in DFI remain low in comparison to data concerning SSTIs [[127]] (e.g., the epidemic furuncles (42%), major abscesses (73%) and gold surgically-drained abscesses (89%)) [[146],[150],[151],[152]]. Indeed, in DFI, a higher incidence of PVL-positive isolates among subjects with CA-MRSA could be observed (31.8% versus 5.7%; p = 0.004) [[153]].

The role of PVL in DFI remains under debate. The different PVL clones are equally distributed among each grade [[122]]. The majority of Grade 1 ulcers where PVL-positive strains were isolated had a rapid amelioration [[122]], and for instance, in Algeria, all of the patients harboring PVL-positive strains isolated from DFI had a worsening evolution. However, the management of chronic wound infections in this country is clearly different from international recommendations, and the use of amputations is frequent, independent of the evolution of the wound. Finally, it is interesting to note that strains isolated from DFOM harbor neither lukF- nor lukS-PV [[154]]. Thus PVL-positive strains are scarce in wound ulcers, and their pathogenicity is not clearly established.

LukED exhibits toxicity toward PMNs in vitro and induces dermatonecrosis when purified toxin is injected into rabbits [[118],[119]]. Moreover, this toxin plays a critical role in S. aureus lethality for mice. It targets and kills murine phagocytes (monocytes-macrophages and neutrophils), promoting disease progression [[155]]. In uninfected DFU, LukED is equally distributed among grades (52%–66%) when we pooled all of the data (Table 2). However, when data are analyzed separately, we showed that the lukDE gene was significantly more often associated with strains isolated from infected ulcers (Grades 2–4) [[122]]. In a more recent study, this gene was clearly identified as a marker that differentiated uninfected from infected ulcers and predicted the outcome of Grade 1 DFU [[110]]. The association between lukDE and MRSA has been also reported in DFI [[48],[156]]. In DFOM, this gene was present in approximately 40% of strains [[154]]. However, even if experimental analysis showed the virulence potential of this leukotoxin, clinically, it seems to present a poorer activity compared to PVL, and the reduced virulence observed may be a response to atypical local inflammatory reaction [[156]].

The last leukocidin characterized is LukAB/HG. This new member of the S. aureus leukotoxin family contributes to neutrophil killing, promotes the survival of S. aureus in human whole blood, restricts neutrophil-mediated killing and promotes CA-MRSA pathogenesis [[115],[116]]. No data concerning its implication in DFU have been reported.

3.2. Exfoliative Toxins

Exfoliative toxins are serine proteases secreted by S. aureus. Three (ETA, ETB and ETD) out of the four different serotypes of this toxin are linked to human infection. The exfoliatins act as “molecular scissors” facilitating bacterial skin invasion [[157]]. The prevalence of eta and/or etb ranges from 0.5%–3% in MSSA [[157],[158],[159]], whereas around 10% of MRSA are eta-positive [[159]].

In uninfected DFU, the distribution varies among clinical grades (Table 2). Interestingly, strains harboring these genes are three-times more frequent in Grade 4 (13.8%) as compared to Grade 1 (4%) or Grades 2–3 (3.5%). However, each exfoliatin does not have the same representation: if eta and etb are rare (1.3%) or absent, respectively, etd is the most prevalent (3.7%), particularly in strains isolated from Grade 4 (10.6%). In a previous study, we could also note that two of four patients harboring an etd-positive strain present on a Grade 1 ulcer had a worsening evolution [[17]]. Post et al. showed an important presence of eta (13%) and etb (17%) in DFI (no screening of etD was noted) [[144]]. However, as no grade has been reported in this work, it is not possible to link exfoliative genes and the severity of the DFI. Finally, this gene was absent in strains isolated from DFOM [[154]].

3.3. Enterotoxins

Enterotoxins are secreted toxins of ~20–30 kD that belong to the family of superantigens (SAg). These molecules over-induce cytokine production from both T-lymphocytes and macrophages [[107]]. The mechanisms by which staphylococcal enterotoxins work are not well known, but may include the activation of cytokine release, ultimately causing cell death by apoptosis. They contribute significantly to major illnesses [[160],[161]]. A recent classification distinguishes three groups of SAg: staphylococcal enterotoxins (SEs), staphylococcal enterotoxin-like toxins (SEls) and toxic shock-syndrome toxin 1 (TSST-1) [[162]].

3.3.1. Staphylococcal Enterotoxins and Enterotoxin-Like Toxins

The majority of S. aureus isolated from DFU have the capacity to produce a large number of Sags, notably SEs and SEls [[161]]. These toxins activate T cells, resulting in a high secretion of proinflammatory cytokines. This process leads to a chronic inflammatory state in uninfected DFUs, inducing a delay or an absence of wound healing [[163]]. Genes, including the sea, sed, seg and sei genes, code for enterotoxins found in S. aureus isolated from DFI. We observed that sea and sei are significantly more prevalent in Grade 2–4 ulcers than in Grade 1 (Table 2) [[122]] and could represent a biomarker to differentiate infection and colonization. The majority of enterotoxins are more frequently identified in MRSA strains except for seb and seh genes [[122]]. One of the main enterotoxins is SED, present in around 40% of the strains [[122],[161]]. The sed gene is often located on a plasmid, and the active protein is structurally similar to SEA [[164]]. SEA could have a major role in atopic dermatitis by inducing the upregulation of adhesion molecules and eliciting inflammatory responses in endothelial cells and keratinocytes [[165]]. Thus, SED may be selected in DFU isolates because, similar to SEA, it has an enhanced ability to induce local inflammatory responses.

3.3.2. Toxic Shock-Syndrome Toxin 1

The best known S. aureus superantigen is the 22-kD toxic shock-syndrome toxin 1 (TSST-1), which causes toxic shock syndrome (TSS). Additionally, SEl-X is a new member of the S. aureus SAg family, and it has been shown to have an important role in S. aureus necrotizing pneumonia infection caused by USA300 MRSA strain [[166]]. Vu et al. found that 88% of the DFU isolates carried the gene for SEl-X; the remainder contained the gene for TSST-1, and one isolate had genes for both SEl-X and TSST-1. Typically, S. aureus strains have the gene for either SEl-X or TSST-1 [[161]]. The prevalence of the tsst gene is low in the strains isolated from diabetic foot (~8%). However, as we observed for etD, this gene is more frequently present in Grade 4 (Table 2) and absent in DFOM [[154]].

3.4. Epidermal Cell Differentiation Inhibitors Toxins

EDINs toxins are members of a group of major bacterial virulence factors targeting host Rho GTPases [[167]]. Recent findings suggest that EDIN toxins might favor bacterial dissemination in tissues by a hematogenous route, through the induction of large transcellular tunnels in endothelial cells named macroapertures [[168],[169],[170]]. Indeed, recent data showed that EDIN toxins promote the formation of infection foci in a mouse model of bacteremia [[171]]. To date, three isoforms of EDIN have been characterized: the first discovered EDIN isoform (EDIN-A), isolated from the E-1 strain of S. aureus [[172]], as well as EDIN-B [[173],[174]] and EDIN-C [[175]]. A first epidemiological survey, involving staphylococcal strains isolated from patients hospitalized for various infectious diseases, demonstrated a higher prevalence of edin-encoding genes in this group compared to nasal strains isolated from healthy patients [[176]]. Munro et al. showed that 90% of all edin-bearing S. aureus isolates carry the type-C allele. These isolates are more significantly associated with deep-seated soft tissue infections than other types of infections [[177]].

Messad et al. analyzed the distribution of edin genes in S. aureus isolated from DFI in a French national collection. edin-B is the most prevalent edin gene associated with DFIs (Table 2) [[17]]. The clonal complex analysis indicated that edin-positive strains belonged to four major groups: a singleton near CC8 (edin-A), a singleton belonging to ST152-MSSA (edin-B), CC80-MRSA (edin-B) and the most prevalent CC25/28-MSSA (edin-B). The distribution of edin genes in DFI shows an important presence of these genes in strains isolated from Grade 4 ulcers (2.5% for Grades 2–3 vs. 10.6% for Grade 4). Of note, patients with Grade 1 ulcers that presented edin-positive strains had a worsening evolution [[17]]. However, these genes seem to be absent in strains isolated from DFOM [[154]]. These observations support the idea that EDIN might work together with the arsenal of S aureus virulence factors to give the bacteria a higher potential for systemic infection [[168]]. edin encoding genes thus represent additional markers of interest to differentiate infecting from colonizing S. aureus strains in DFU and to predict the wound outcome.

4. Conclusions

In conclusion, DFI is a complex pathology involving the virulence of bacteria and host responses. Indeed, its main feature is the coexistence of multiple bacterial species on the chronic wound organized in pathogroups and the host-related responses encountered by bacteria, which modify the bacterial pathogenicity. Some studies showed the presence of toxinogenic S. aureus strains (harboring exfoliatins-, EDIN-, PVL- or TSST-encoding genes) in DFI, notably in Grade 4, with systemic impact. The absence of the same strains in DFOM suggests that these strains may not be adapted to colonize wounds. On the other hand, the main population of S. aureus (non-toxinogenic) isolated in uninfected DFU is perfectly adapted to infect deep structures and bone. The rarity of systemic cases (Grade 4) and of the presence of toxinogenic bacteria would, by definition, be an infected wound. However, it is interesting to note that some toxinogenic strains with a high pathogenic potential are present on uninfected wounds promoting no virulence in this polymicrobial environment. Moreover, no clear link between these strains and amputations has been noted to date. Subsequent studies are required to understand the role of toxins and their real impact in DFU. Screening the presence of genes encoding toxins by molecular biology tests on uninfected DFU could also represent a new approach for patients for whom the clinical diagnosis of infection is hampered by peripheral arterial disease, neuropathy or impaired leukocyte functions in the aim to predict if S. aureus is going to be invasive or not (needing an antibiotic treatment).

Acknowledgements

Acknowledgments

U1047 Team was supported by INSERM (Institut National de la Sante et de la Recherche Medicale).

References

  1. N. SinghD.G. ArmstrongB.A. LipskyPreventing foot ulcers in patients with diabetesJAMA200529321722810.1001/jama.293.2.21715644549
  2. L. PrompersM. HuijbertsN. SchaperJ. ApelqvistK. BakkerM. EdmondsP. HolsteinE. JudeA. JirkovskaD. MauricioResource utilisation and costs associated with the treatment of diabetic foot ulcers. Prospective data from the Eurodiale StudyDiabetologia2008511826183410.1007/s00125-008-1089-618648766
  3. B.A. LipskyA.R. BerendtH.G. DeeryJ.M. EmbilW.S. JosephA.W. KarchmerJ.L. LeFrockD.P. LewJ.T. MaderC. NordenDiagnosis and treatment of diabetic foot infectionsClin. Infect. Dis.20043988591010.1086/42484615472838
  4. L.A. LaveryD.G. ArmstrongR.P. WunderlichJ. TredwellA.J. BoultonDiabetic foot syndrome: Evaluating the prevalence and incidence of foot pathology in Mexican Americans and non-Hispanic whites from a diabetes disease management cohortDiabetes Care2003261435143810.2337/diacare.26.5.143512716801
  5. W.J. JeffcoateB.A. LipskyA.R. BerendtP.R. CavanaghS.A. BusE.J. PetersW.H. van HoutumG. ValkK. BakkerUnresolved issues in the management of ulcers of the foot in diabetesDiabet. Med.2008251380138910.1111/j.1464-5491.2008.02573.x19046235
  6. L.A. LaveryD.G. ArmstrongR.P. WunderlichM.J. MohlerC.S. WendelB.A. LipskyRisk factors for foot infections in individuals with diabetesDiabetes Care2006291288129310.2337/dc05-242516732010
  7. J.L. RichardJ.P. LavigneA. SottoDiabetes and foot infection: More than double troubleDiabetes Metab. Res. Rev.201228465310.1002/dmrr.223422271723
  8. A. SpichlerB.L. HurwitzD.G. ArmstrongB.A. LipskyMicrobiology of diabetic foot infections: From Louis Pasteur to “crime scene investigation”BMC Med.20151320910.1186/s12916-014-0232-026335923
  9. J.P. LavigneA. SottoC. Dunyach-RemyB.A. LipskyNew molecular techniques to study the skin microbiota of diabetic foot ulcersAdv. Wound Care20154384910.1089/wound.2014.053225566413
  10. M. EdmondsInfection in the neuroischemic footInt. J. Low. Extrem. Wounds2005414515310.1177/153473460528059716100095
  11. D.T. WilliamsJ.R. HiltonK.G. HardingDiagnosing foot infection in diabetesClin. Infect. Dis.200439S83S8610.1086/38326715306984
  12. D.G. ArmstrongL.A. LaveryM. SariayaH. AshryLeukocytosis is a poor indicator of acute osteomyelitis of the foot in diabetes mellitusJ. Foot Ankle Surg.19963528028310.1016/S1067-2516(96)80075-58872749
  13. M. EnerothJ. LarssonJ. ApelqvistDeep foot infections in patients with diabetes and foot ulcer: An entity with different characteristics, treatments, and prognosisJ. Diabetes Complicat.19991325426310.1016/S1056-8727(99)00065-310764999
  14. M. EnerothJ. ApelqvistA. StenströmClinical characteristics and outcome in 223 diabetic patients with deep foot infectionsFoot Ankle Int.19971871672210.1177/1071100797018011079391817
  15. B.A. LipskyInternational consensus group on diagnosing and treating the infected diabetic foot. A report from the international consensus on diagnosing and treating the infected diabetic footDiabetes Metab. Res. Rev.200420S68S7710.1002/dmrr.45315150818
  16. J.L. RichardA. SottoJ.P. LavigneNew insights in diabetic foot infectionWorld J. Diabetes201115243210.4239/wjd.v2.i2.2421537457
  17. N. MessadL. LandraudB. CanivetG. LinaJ.L. RichardA. SottoJ.P. LavigneDistribution of edin in Staphylococcus aureus isolated from diabetic foot ulcersClin. Microbiol. Infect.20131987588010.1111/1469-0691.1208423176291
  18. S.E. GardnerS.L. HillisK. HeilmannJ.A. SegreE.A. GriceThe neuropathic diabetic foot ulcer microbiome is associated with clinical factorsDiabetes20136292393010.2337/db12-077123139351
  19. M. HatipogluM. MutluogluV. TurhanG. UzunB.A. LipskyTurk-DAY Study GroupE. SevimH. DemiraslanE. EryilmazC. OzuguzCausative pathogens and antibiotic resistance in diabetic foot infections: A prospective multi-center studyJ. Diabetes Complicat.20163091091610.1016/j.jdiacomp.2016.02.01326965794
  20. R.J. CommonsC.H. RobinsonD. GawlerJ.S. DavisR.N. PriceHigh burden of diabetic foot infections in the top end of Australia: An emerging health crisis (DEFINE study)Diabetes Res. Clin. Pract.201511014715710.1016/j.diabres.2015.09.01626453263
  21. O. LesensF. DesbiezC. TheïsT. FerryM. BensalemH. LaurichesseI. TauveronJ. BeytoutJ. Aragón-SánchezWorking Group on Diabetic OsteomyelitisStaphylococcus aureus-related diabetic osteomyelitis: Medical or surgical management? A French and Spanish retrospective cohortInt. J. Low. Extrem. Wounds20151428429010.1177/153473461455993125515373
  22. R. SerraR. GrandeL. ButricoA. RossiU.F. SettimioB. CaroleoB. AmatoL. GallelliS. de FranciscisChronic wound infections: The role of Pseudomonas aeruginosa and Staphylococcus aureusExpert Rev. Anti-Infect. Ther.20151360561310.1586/14787210.2015.102329125746414
  23. H.F. WertheimD.C. MellesM.C. VosW. van LeeuwenA. van BelkumH.A. VerbrughJ.L. NouwenThe role of nasal carriage in Staphylococcus aureus infectionsLancet Infect. Dis.2005575176210.1016/S1473-3099(05)70295-416310147
  24. S.Y. TongJ.S. DavidE. EichenbergerT.L. HollandV.G. Fowler Jr.Staphylococcus aureus infections: Epidemiology, pathophysiology, clinical manifestations, and managementClin. Microbiol. Rev.20152860366110.1128/CMR.00134-1426016486
  25. B.A. LipskyJ. Aragon-SanchezJ. EmbilS. KonoL. LaveryE. SennevilleV. Urbancic-RovanS. Van AstenE.J.G. PetersInternational Working Group on the Diabetic Foot (IWGDF)IWGDF guidance on the diagnosis and management of foot infections in persons with diabetesDiabetes Metab. Res. Rev.201632457410.1002/dmrr.269926386266
  26. N.C. ShaperDiabetic foot ulcer classification system for research purposes: A progress report on criteria for including patients in research studiesDiabetes Metab. Res. Rev.200420S90S9510.1002/dmrr.46415150820
  27. B.A. LipskyA.R. BerendtP.B. CorniaJ.C. PileE.J. PetersD.G. ArmstrongH.G. DeeryJ.M. EmbilW.S. JosephA.W. Karchmer2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infectionsJ. Am. Podiatr. Med. Assoc.20131032710.7547/103000223328846
  28. B.A. LipskyOsteomyelitis of the foot in diabetic patientsClin. Infect. Dis.1997251318132610.1086/5161489431370
  29. A. MarkandayDiagnosing diabetic foot osteomyelitis: Narrative review and a suggested 2-step score-based diagnostic pathway for cliniciansOpen Forum Infect. Dis.20141ofu06010.1093/ofid/ofu06025734130
  30. L.G. NewmanJ. WallerC.J. PalestroM. SchwartzM.J. KleinG. HermannE. HarringtonM. HarringtonS.H. RomanA. Stagnaro-GreenUnsuspected osteomyelitis in diabetic foot ulcers. Diagnosis and monitoring by leukocyte scanning with indium in 111 oxyquinolineJAMA19912661246125110.1001/jama.1991.034700900800361908030
  31. J.L. LazaroV. IzzoS. MeaumeA.H. DaviesR. LobmannL. UccioliElevated levels of matrix metalloproteinases and chronic wound healing: An updated review of clinical evidenceJ. Wound Care20162527728710.12968/jowc.2016.25.5.27727169343
  32. S.M. McCartyC.A. CochraneP.D. CleggS.L. PercivalThe role of endogenous and exogenous enzymes in chronic wounds: A focus on the implications of aberrant levels of both host and bacterial proteases in wound healingWound Repair Regen.20122012513610.1111/j.1524-475X.2012.00763.x22380687
  33. Y. RenG. GuM. YaoV.R. DriverRole of matrix metalloproteinases in chronic wound healing: Diagnostic and therapeutic implicationsChin. Med. J.20141271572158124762608
  34. M. ChangRestructuring of the extracellular matrix in diabetic wounds and healing: A perspectivePharmacol. Res.201610724324810.1016/j.phrs.2016.03.00827033051
  35. R. VisseH. NagaseMatrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistryCirc. Res.20039282783910.1161/01.RES.0000070112.80711.3D12730128
  36. Z. LiS. GuoF. YaoY. ZhangT. LiIncreased ratio of serum matrix metalloproteinase-9 against TIMP-1 predicts poor wound healing in diabetic foot ulcersJ. Diabetes Complicat.20132738038210.1016/j.jdiacomp.2012.12.00723357650
  37. D.R. YagerL.Y. ZhangH.X. LiangR.F. DiegelmannI.K. CohenWound fluids from human pressure ulcers contain elevated matrix metalloproteinase levels and activity compared to surgical wound fluidsJ. Investig. Dermatol.199610774374810.1111/1523-1747.ep123656378875960
  38. S. SaitoM.J. TrovatoR. YouB.K. LalF. FasehunF.T. Padberg Jr.R.W. Hobson 2ndW.N. DuránP.J. PappasRole of matrix metalloproteinases 1, 2, and 9 and tissue inhibitor of matrix metalloproteinase-1 in chronic venous insufficiencyJ. Vasc. Surg.20013493093810.1067/mva.2001.11950311700497
  39. R. LobmannA. AmbroschG. SchultzK. WaldmannS. SchiweckH. LehnertExpression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patientsDiabetologia2002451011101610.1007/s00125-002-0868-812136400
  40. F. GrinnellM. ZhuFibronectin degradation in chronic wounds depends on the relative levels of elastase, alpha1-proteinase inhibitor, and alpha2-macroglobulinJ. Investig. Dermatol.199610633534110.1111/1523-1747.ep123429908601737
  41. N. TentolourisG. PetrikkosN. VallianouC. ZachosG.L. DaikosP. TsapogasG. MarkouN. KatsilambrosPrevalence of methicillin-resistant Staphylococcus aureus in infected and uninfected diabetic foot ulcersClin. Microbiol. Infect.20061218618910.1111/j.1469-0691.2005.01279.x16441460
  42. F. GameW. JeffcoateMRSA and osteomyelitis of the foot in diabetesDiabet. Med.200421161910.1111/j.1464-5491.2004.1424-8.x15315521
  43. C.N. DangY.D. PrasadA.J. BoultonE.B. JudeMethicillin-resistant Staphylococcus aureus in the diabetic foot clinic: A worsening problemDiabet. Med.20032015916110.1046/j.1464-5491.2003.00860.x12581269
  44. N.R. BarshesM.C. Rodriguez-BarradasC.F. BecharaG. PisimisisE.J. YoungP. KougiasMicrobial isolates and their antimicrobial susceptibilities in inframalleolar foot infectionsSurg. Infect.20141558559110.1089/sur.2013.12624827989
  45. D.M. CitronE.J. GoldsteinC.V. MerriamB.A. LipskyM.A. AbramsonBacteriology of moderate-to-severe diabetic foot infections and in vitro activity of antimicrobial agentsJ. Clin. Microbiol.2007452819282810.1128/JCM.00551-0717609322
  46. L.A. LaveryL.B. HarklessK. Felder-JohnsonS. MundineBacterial pathogens in infected puncture wounds in adults with diabetesJ. Foot Ankle Surg.19943391978162001
  47. L.A. LaveryM. SariayaH. AshryL.B. HarklessMicrobiology of osteomyelitis in diabetic foot infectionsJ. Foot Ankle Surg.199534616410.1016/S1067-2516(09)80103-87780395
  48. N. DjahmiN. MessadS. NedjaiA. MoussaouiD. MazouzJ.L. RichardA. SottoJ.P. LavigneMolecular epidemiology of Staphylococcus aureus strains isolated from inpatients with infected diabetic foot ulcers in an Algerian University HospitalClin. Microb. Infect.201319E398E40410.1111/1469-0691.1219923521557
  49. J.L. RichardJ.P. LavigneI. GotA. HartemannD. MalgrangeD. TsirtsikolouA. BaleydierE. SennevilleManagement of patients hospitalized for diabetic foot infection: Results of the French OPIDIA studyDiabetes Metab.20113720821510.1016/j.diabet.2010.10.00321169044
  50. K. Al BenwanA. Al MullaV.O. RotimiA study of the microbiology of diabetic foot infections in a teaching hospital in KuwaiJ. Infect. Public Health201251810.1016/j.jiph.2011.07.00422341838
  51. M.T. AkhiR. GhotaslouM. AsgharzadehM. VarshochiT. PirzadehM.Y. MemarA. Zahedi BialvaeiH. Seifi Yarijan SoflaN. AlizadehBacterial etiology and antibiotic susceptibility pattern of diabetic foot infections in Tabriz, IranGMS Hyg. Infect. Control201510Doc0210.3205/dgkh00024525699225
  52. M. AnvarinejadG. PouladfarA. JaponiS. BolandparvazZ. SatiaryP. AbbasiJ. MardanehIsolation and antibiotic susceptibility of the microorganisms isolated from diabetic foot infections in Nemazee Hospital, Southern IranJ. Pathog.2015201510.1155/2015/32879626843987
  53. S.M. AlaviA.D. KhosraviA. SaramiA. DashtebozorgE.A. MontazeriBacteriologic study of diabetic foot ulcerPak. J. Med. Sci.200723568168410.1016/j.ijid.2008.05.519
  54. N.S. RajaMicrobiology of diabetic foot infections in a teaching hospital in Malaysia: A retrospective study of 194 casesJ. Microbiol. Immunol. Infect.200740394417332905
  55. R. YogaA. KhairulK. SunitaC. SureshBacteriology of diabetic foot lesionsMed. J. Malays.2006611416
  56. A. Martinez-Gomez DdeC. Ramirez-AlmagroA. Campillo-SotoG. Morales-CuencaJ. Pagan-OrtizJ.L. Aguayo-AlbasiniDiabetic foot infections. Prevalence and antibiotic sensitivity of the causative microorganismsEnferm. Infecc. Microbiol. Clin.20092731732119237227
  57. M.C. PerimC. Bordes JdaS.R. CelesteF. Orsolin EdeR.R. MendesG.O. MendesR.L. FerreiraS.C. CarreiroM.C. PrancheviciusAerobic bacterial profile and antibiotic resistance in patients with diabetic foot infectionsRev. Soc. Bras. Med. Trop.20154854655410.1590/0037-8682-0146-201526516963
  58. P. ShanmugamM. JeyaS. Linda SusanThe bacteriology of diabetic foot ulcers, with a special reference to multidrug resistant strainsJ. Clin. Diagn. Res.2013744144510.7860/JCDR/2013/5091.279423634392
  59. P. SugandhiD.A. PrasanthMicrobiological profile of bacterial pathogens from diabetic foot infections in tertiary care hospitals, SalemDiabetes Metab. Syndr.2014812913210.1016/j.dsx.2014.07.00425087885
  60. T. MathangiP. PrabhakaranF. RayappanF. TiltonIsolation, molecular characterization and antibiogram of bacteria isolated from DFUInt. J. Curr. Res. Acad. Rev.201311725
  61. S.M. SekharN. VyasM.K. UnnikrishnanG.S. RodriguesC. MukhopadhyayAntimicrobial susceptibility pattern in diabetic foot ulcer: A pilot studyAnn. Med. Health Sci. Res.2014474274510.4103/2141-9248.14154125328786
  62. S.H. WangZ.L. SunY.J. GuoB.Q. YangY. YuanQ. WeiK.P. YeMeticillin-resistant Staphylococcus aureus isolated from foot ulcers in diabetic patients in a Chinese care hospital: Risk factors for infection and prevalenceJ. Med. Microbiol.2010591219122410.1099/jmm.0.020537-020595400
  63. Q. DingD.Q. LiP.H. WangY.J. ChuS.Y. MengQ. SunRisk factors for infections of methicillin-resistant Staphylococci in diabetic foot patientsZhonhua Yi Xue Za Zhi201292228231
  64. V.K. SharmaP.B. KhadkaA. JoshiR. SharmaCommon pathogens isolated in diabetic foot infection in Bir HospitalKathmandu Univ. Med. J.20064295301
  65. S. IslamS.O. CawichS. BudhooramP. HarnarayanV. MahabirS. RamsewakV. NaraynsinghMicrobial profile of diabetic foot infections in Trinidad and TobagoPrim. Care Diabetes2013730330810.1016/j.pcd.2013.05.00123742849
  66. J.J. MendesA. Marques-CostaC. VilelaJ. NevesN. CandeiasP. Cavaco-SilvaJ. Melo-CristinoClinical and bacteriological survey of diabetic foot infections in LisbonDiabetes Res. Clin. Pract.20129515316110.1016/j.diabres.2011.10.00122019426
  67. M. RadjiC.S. PutriS. FauziyahAntibiotic therapy for diabetic foot infections in a tertiary care hospital in Jakarta, IndonesiaDiabetes Metab. Syndr.2014822122410.1016/j.dsx.2014.09.00625311820
  68. A.T. El-TahawyBacteriology of diabetic footSaudi Med. J.20002134434711533815
  69. O. GuiraH. TiénoS. TraoréI. DialloE. OuangréY. SagnaJ. ZabsonréD. YanogoS.S. TraoréY.J. DraboThe bacterial microflora of diabetic foot infection and factors determining its spectrum in Ouagadougou (Burkina Faso)Bull. Soc. Pathol. Exot.201510830731110.1007/s13149-015-0442-526187771
  70. C.N. UnachukwuO.K. ObungeO.J. OdiaThe bacteriology of diabetic foot ulcers in Port Harcourt, NigeriaNiger. J. Med.20051417317616083241
  71. D.E. KatzN.D. FriedmanE. OstrovskiD. RavidN. AmramiD. AviviB. MengeshaR. ZaidensteinT. LazarovitchM. DadonDiabetic foot infection in hospitalized adultsJ. Infect. Chemother.20162216717310.1016/j.jiac.2015.12.00726806149
  72. E. Cervantes-GarciaR. García-GonzálezA. Reséndiz-AlborP.M. Salazar-SchettinoInfections of diabetic foot ulcers with methicillin-resistant Staphylococcus aureusInt. J. Low. Extrem. Wounds201514444910.1177/153473461456405325573977
  73. H. LelievreG. LinaM.E. JonesC. OliveF. ForeyM. Roussel-DelvallezM.H. Nicolas-ChanoineC.M. BébéarV. JarlierA. AndremontEmergence and spread in French hospitals of methicillin-resistant Staphylococcus aureus with increasing susceptibility to gentamicin and other antibioticsJ. Clin. Microbiol.1999373452345710523533
  74. B.M. ErtugrulO. OnculN. TulekA. WillkeS. SacarO.G. TunccanE. YilmazO. KayaB. OzturkO. TurhanA prospective, multi-center study: Factors related to the management of diabetic foot infectionsEur. J. Clin. Microbiol. Infect. Dis.2012312345235210.1007/s10096-012-1574-122354524
  75. R. LeclercqEpidemiological and resistance issues in multidrug-resistant staphylococci and enterococciClin. Microbiol. Infect.20091522423110.1111/j.1469-0691.2009.02739.x19335370
  76. Société de Pathologie Infectieuse de Langue FrançaiseManagement of diabetic foot infections. Short textMed. Mal. Infect.200737125
  77. American Diabetes AssociationConsensus development conference on diabetic foot wound careDiabetes Care1999221354136010480782
  78. I. EleftheriadouN. TentolourisV. ArgianaE. JudeA.J. BoultonMethicillin-resistant Staphylococcus aureus in diabetic foot infectionsDrugs2010701785179710.2165/11538070-000000000-0000020836573
  79. P.R. Lagacé-WiensD. OrmistonL.E. NicolleT. HildermanJ. EmbilThe diabetic foot clinic: Not a significant source for acquisition of methicillin-resistant Staphylococcus aureusAm. J. Infect. Control20093758758910.1016/j.ajic.2008.11.00619243857
  80. D. PittetS. HugonnetS. HarbarthP. MourougaV. SauvanS. TouveneauT.V. PernegerEffectiveness of a hospital-wide programme to improve compliance with hand hygieneLancet20003561307131210.1016/S0140-6736(00)02814-211073019
  81. B. ZenelajC. BouvetB.A. LipskyI. UçkayDo diabetic foot infections with methicillin-resistant Staphylococcus aureus differ from those with other pathogens?Int. J. Low. Extrem. Wounds20141326327210.1177/153473461455031125288579
  82. J.L. RichardA. SottoN. JourdanC. CombescureD. VannereauM. RodierJ.P. LavigneRisk factors and healing impact of multidrug-resistant bacteria in diabetic foot ulcersDiabetes Metab.20083436336910.1016/j.diabet.2008.02.00518632297
  83. J. Aragón-SánchezJ.L. Lázaro-MartínezY. Quintana-MarreroM.J. Hernández-HerreroE. García-MoralesJ.J. Cabrera-GalvánJ.V. Beneit-MontesinosAre diabetic foot ulcers complicated by MRSA osteomyelitis associated with worse prognosis? Outcomes of a surgical seriesDiabet. Med.20092655255510.1111/j.1464-5491.2009.02714.x19646197
  84. S. ChangD.M. SievertJ.C. HagemanM.L. BoultonF.C. TenoverF.P. DownesS. ShahJ.T. RudrikG.R. PuppW.J. BrownInfection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance geneN. Engl. J. Med.20033481342134710.1056/NEJMoa02502512672861
  85. A. DezfulianM.M. AslaniM. OskouiP. FarrokhM. AzimiradH. DabiriM.T. SalehianM.R. ZaliIdentification and characterization of a high vancomycin-resistant Staphylococcus aureus harboring vanA gene cluster isolated from diabetic foot ulcerIran. J. Basic Med. Sci.20121580380623495359
  86. T.J. FosterImmune evasion by staphylococciNat. Rev. Microbiol.2005394895810.1038/nrmicro128916322743
  87. A. AmbroschS. HaefnerE. JudeR. LobmannDiabetic foot infections: Microbiological aspects, current and future antibiotic therapy focusing on methicillin-resistant Staphylococcus aureusInt. Wound J.2011856757710.1111/j.1742-481X.2011.00849.x21883937
  88. R. CunninghamA. CockayneH. HumphreysClinical and molecular aspects of the pathogenesis of Staphylococcus aureus bone and joint infectionsJ. Med. Microbiol.19964415716410.1099/00222615-44-3-1578636931
  89. S.R. ClarkeK.J. BrummellM.J. HorsburghP.W. McDowellS.A. MohamadM.R. StapletonJ. AcevedoR.C. ReadN.P. DayS.J. PeacockIdentification of in vivo-expressed antigens of Staphylococcus aureus and their use in vaccinations for protection against nasal carriageJ. Infect. Dis.20061931098110810.1086/50147116544250
  90. C. WeidenmaierJ.F. Kokai-KunS.A. KristianT. ChanturiyaH. KalbacherM. GrossG. NicholsonB. NeumeisterJ.J. MondA. PeschelRole of teichoic acids in Staphylococcus aureus nasal colonization, a major risk factor in nosocomial infectionsNat. Med.20041024324510.1038/nm99114758355
  91. M. BurianM. RautenbergT. KohlerM. FritzB. KrismerC. UngerW.H. HoffmannA. PeschelC. WolzC. GoerkeTemporal expression of adhesion factors and activity of global regulators during establishment of Staphylococcus aureus nasal colonizationJ. Infect. Dis.20102011414142110.1086/65161920307206
  92. S.H. ChoI. StricklandM. BoguniewiczD.Y. LeungFibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skinJ. Allergy Clin. Immunol.200110826927410.1067/mai.2001.11745511496245
  93. S. ShiX. ZhangInteraction of Staphylococcus aureus with osteoblastsExp. Ther. Med.2012336737022969897
  94. R.A. ProctorC. von EiffB.C. KahlK. BeckerP. McNamaraM. HerrmannG. PetersSmall colony variants: A pathogenic form of bacteria that facilitates persistent and recurrent infectionsNat. Rev. Microbiol.2006429530510.1038/nrmicro138416541137
  95. L. TuchscherrV. HeitmannM. HussainD. ViemannJ. RothC. von EiffG. PetersK. BeckerB. LöfflerStaphylococcus aureus small-colony variants are adapted phenotypes for intracellular persistenceJ. Infect. Dis.20102021031104010.1086/65604720715929
  96. C. Von EiffK. BeckerD. MetzeG. LubritzJ. HockmannT. SchwarzG. PetersIntracellular persistence of Staphylococcus aureus small-colony variants within keratinocytes: A cause for antibiotic treatment failure in a patient with darier’s diseaseClin. Infect. Dis.2001321643164710.1086/32051911340539
  97. N. BaumertC. von EiffF. SchaaffG. PetersR.A. ProctorH.G. SahlPhysiology and antibiotic susceptibility of Staphylococcus aureus small colony variantsMicrob. Drug Res.2002825326010.1089/1076629026046950712523621
  98. L.G. GarciaS. LemaireB.C. KahlK. BeckerR.A. ProctorO. DenisP.M. TulkensF. Van BambekeAntibiotic activity against small-colony variants of Staphylococcus aureus: Review of in vitro, animal and clinical dataJ. Antimicrob. Chemother.2013681455146410.1093/jac/dkt07223485724
  99. R.A. ProctorG. PetersSmall colony variants in staphylococcal infections: Diagnostic and therapeutic implicationsClin. Infect. Dis.19982741942210.1086/5147069770133
  100. A. PodbielskaH. GalbowskaE. StelmachG. MlynarczykW.L. OlszewskiSlime production by Staphylococcus aureus and Staphylococcus epidermidis strains isolated from patients with diabetic foot ulcersArch. Immunol. Ther. Exp.20105832132410.1007/s00005-010-0079-920502972
  101. T.M. BergaminiR.A. CorpusK.L. HoegK.R. BrittianJ.C. PeytonW.G. CheadleImmune regulation of bacterial biofilm graft infectionASAIO J.19944021922610.1097/00002480-199440020-000188003763
  102. D. SteinbergS. PoranL. ShapiraThe effect of extracellular polysaccharides from Streptococcus mutans on the bactericidal activity of human neutrophilsArch. Oral Biol.19994443744410.1016/S0003-9969(99)00014-X10391502
  103. H. YasudaY. AjikiJ. AoyamaT. YokotaInteraction between human polymorphonuclear leucocytes and bacteria released from in vitro bacterial biofilm modelsJ. Med. Microbiol.19944135936710.1099/00222615-41-5-3597966209
  104. T. BjarnsholtK. Kirketerp-MollerP.O. JensenK.G. MadsenR. PhilippsK. KrogfeltN. HoibyM. GivskovWhy chronic wounds will not heal: A novel hypothesisWound Repair. Regen.20081621010.1111/j.1524-475X.2007.00283.x18211573
  105. F. VandeneschG. LinaT. HenryStaphylococcus aureus hemolysins, bi-component leukocidins, and cytolytic peptides: A redundant arsenal of membrane-damaging virulence factors?Front. Cell. Infect. Microbiol.201221210.3389/fcimb.2012.0001222919604
  106. D. GrumannU. NubelB.M. BrokerStaphylococcus aureus toxins—Their functions and geneticsInfect. Genet. Evol.20142158359210.1016/j.meegid.2013.03.01323541411
  107. M. OttoStaphylococcus aureus toxinsCurr. Opin. Microbiol.201417323710.1016/j.mib.2013.11.00424581690
  108. Y.Q. XiongJ. WillardM.R. YeamanA.L. CheungA.S. BayerRegulation of Staphylococcus aureus alpha-toxin gene (hla) expression by agr, sarA, and sae in vitro and in experimental infective endocarditisJ. Infect. Dis.20061941267127510.1086/50821017041853
  109. A. ValevaI. WalevM. PinkernellB. WalkerH. BayleyM. PalmerS. BhakdiTransmembrane beta-barrel of staphylococcal alpha-toxin forms in sensitive but not in resistant cellsProc. Natl. Acad. Sci. USA199794116071161110.1073/pnas.94.21.116079326657
  110. A. SottoJ.L. RichardN. MessadN. MolinariN. JourdanS. SchuldinerA. SultanC. CarrièreB. CanivetL. LandraudDistinguishing colonization from infection with Staphylococcus aureus in diabetic foot ulcers with miniaturized oligonucleotide arrays: A French multicenter studyDiabetes Care20123561762310.2337/dc11-135222301121
  111. R. WangK.R. BraughtonD. KretschmerT.H. BachS.Y. QueckM. LiA.D. KennedyD.W. DorwardS.J. KlebanoffA. PeschelIdentification of novel cytolytic peptides as key virulence determinants for community-associated MRSANat. Med.2007131510151410.1038/nm165617994102
  112. M. LiB.A. DiepA.E. VillaruzK.R. BraughtonX. JiangF.R. DeLeoH.F. ChambersY. LuM. OttoEvolution of virulence in epidemic community-associated methicillin-resistant Staphylococcus aureusProc. Natl. Acad. Sci. USA20091065883588810.1073/pnas.090074310619293374
  113. S.S. ChatterjeeH.S. JooA.C. DuongT.D. DieringerV.Y. TanY. SongE.R. FischerG.Y. CheungM. LiM. OttoEssential Staphylococcus aureus toxin export systemNat. Med.20131936436710.1038/nm.304723396209
  114. B.G. SurewaardC.J. de HaasF. VervoortK.M. RigbyF.R. DeLeoM. OttoJ.A. van StrijpR. NijlandStaphylococcal alpha-phenol soluble modulins contribute to neutrophil lysis after phagocytosisCell. Microbiol.2013151427143710.1111/cmi.1213023470014
  115. A.L. DumontT.K. NygaardR.L. WatkinsA. SmithL. KozhayaB.N. KreiswirthB. ShopsinD. UnutmazJ.M. VoyichV.J. TorresCharacterization of a new cytotoxin that contributes to Staphylococcus aureus pathogenesisMol. Microbiol.20117981482510.1111/j.1365-2958.2010.07490.x21255120
  116. C.L. VenturaN. MalachowaC.H. HammerG.A. NardoneM.A. RobinsonS.D. KobayashiF.R. DeLeoIdentification of a novel Staphylococcus aureus two-component leukotoxin using cell surface proteomicsPLoS ONE2010520910.1371/journal.pone.001163420661294
  117. P.N. PantonF.C.O. ValentineStaphylococcal toxinLancet193221950650810.1016/S0140-6736(01)24468-7
  118. A. GravetD.A. ColinD. KellerR. GirardotH. MonteilG. PrevostCharacterization of a novel structural member, LukE-LukD, of the bi-component staphylococcal leucotoxins familyFEBS Lett.199843620220810.1016/S0014-5793(98)01130-29781679
  119. N. MorinagaY. KaihouM. NodaPurification, cloning and characterization of variant LukE-LukD with strong leukocidal activity of staphylococcal bi-component leukotoxin familyMicrobiol. Immunol.200347819010.1111/j.1348-0421.2003.tb02789.x12636257
  120. I.M. NilssonO. HartfordT. FosterA. TarkowskiAlpha-toxin and gamma-toxin jointly promote Staphylococcus aureus virulence in murine septic arthritisInf. Immun.19996710451049
  121. N. MalachowaA.R. WhitneyS.D. KobayashiD.E. SturdevantA.D. KennedyK.R. BraughtonD.W. ShabbB.A. DiepH.F. ChambersM. OttoGlobal changes in Staphylococcus aureus gene expression in human bloodPLoS ONE2011620910.1371/journal.pone.001861721525981
  122. A. SottoG. LinaJ.L. RichardC. CombescureG. BourgL. VidalN. JourdanJ. EtienneJ.P. LavigneVirulence potential of Staphylococcus aureus strains isolated from diabetic foot ulcersDiabetes Care2008312318232410.2337/dc08-101018809632
  123. S. Boyle-VavraR.S. DaumCommunity-acquired methicillin-resistant Staphylococcus aureus: The role of Panton-Valentine leukocidinLab. Investig.2007873910.1038/labinvest.370050117146447
  124. J. KanekoT. KimuraY. KawakamiT. TomitaY. KamioPanton-valentine leukocidin genes in a phage-like particle isolated from mitomycin C-treated Staphylococcus aureus V8 (ATCC 49775)Biosci. Biotechnol. Biochem.1997611960196210.1271/bbb.61.19609404084
  125. S. NaritaJ. KanekoJ. ChibaY. PiemontS. JarraudJ. EtienneY. KamioPhage conversion of Panton-Valentine leukocidin in Staphylococcus aureus: Molecular analysis of a PVL-converting phage, phiSLTGene200126819520610.1016/S0378-1119(01)00390-011368915
  126. C. DupieuxR. BlondéC. BouchiatH. MeugnierM. BesS. LaurentF. VandeneschF. LaurentA. TristanCommunity-acquired infections due to Staphylococcus argenteus lineage isolates harbouring the Panton-Valentine leucocidin, France, 2014Euro Surveill.2015202115410.2807/1560-7917.ES2015.20.23.2115426084314
  127. L.J. ShallcrossE. FragaszyA.M. JohnsonA.C. HaywardThe role of the Panton-Valentine leucocidin toxin in staphylococcal disease: A systematic review and meta-analysisLancet Infect. Dis.201313435410.1016/S1473-3099(12)70238-423103172
  128. Y. GilletB. IssartelP. VanhemsJ.C. FournetG. LinaM. BesF. VandeneschY. PiemontN. BrousseD. FloretAssociation between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patientsLancet200235975375910.1016/S0140-6736(02)07877-711888586
  129. F. VandeneschT. NaimiM.C. EnrightG. LinaG.R. NimmoH. HeffernanN. LiassineM. BesT. GreenlandM.E. ReverdyCommunity- acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: Worldwide emergenceEmerg. Infect. Dis.2003997898410.3201/eid0908.03008912967497
  130. S.K. ShuklaM.E. KarowJ.M. BradyM.E. StemperJ. KislowN. MooreK. WroblewskiP.H. ChyouD.M. WarshauerK.D. ReedVirulence genes and genotypic associations in nasal carriage, community-associated methicillin- susceptible and methicillin-resistant USA400 Staphylococcus aureus isolatesJ. Clin. Microbiol.2010483582359210.1128/JCM.00657-1020668125
  131. A. KiliçE. DoğanS. KayaM. BaysallarInvestigation of the presence of mecC and Panton-Valentine leukocidin genes in Staphylococcus aureus strains isolated from clinical specimens during seven years periodMikrobiyol. Bulteni20154959459910.5578/mb.9871
  132. D. SantosaningsihS. SantosoN.S. BudayantiK. SuataE.S. LestariH. WahjonoA. DjamalK. KuntamanA. van BelkumM. LaurensCharacterisation of clinical Staphylococcus aureus isolates harbouring mecA or Panton-Valentine leukocidin genes from four tertiary care hospitals in IndonesiaTrop. Med. Int. Health20162161061810.1111/tmi.1269226970318
  133. H. MotamediS.S. Rahmat AbadiS.M. MoosavianM. TorabiThe association of Panton-Valentine leukocidin and mecA genes in Methicillin-Resistant Staphylococcus aureus isolates from patients referred to Educational Hospitals in Ahvaz, IranJundishapur J. Microbiol.20158e2202110.5812/jjm.22021v226468365
  134. F. YuY. LiuJ. LvX. QiC. LuY. DingD. LiH. LiuL. WangAntimicrobial susceptibility, virulence determinant carriage and molecular characteristics of Staphylococcus aureus isolates associated with skin and soft tissue infectionsBraz. J. Infect. Dis.20151961462210.1016/j.bjid.2015.08.00626408338
  135. T. ConceiçãoC. CoelhoH. de LencastreM. Aires-de-SousaFrequent occurrence of oxacillin-susceptible mecA-positive Staphylococcus aureus (OS-MRSA) strains in two African countriesJ. Antimicrob. Chemother.2015703200320426318189
  136. B. ChenX. DaiB. HeK. PanH. LiX. LiuY. BaoW. LaoX. WuY. YaoS. HuangDifferences in Staphylococcus aureus nasal carriage and molecular characteristics among community residents and healthcare workers at Sun Yat-Sen University, Guangzhou, Southern ChinaBMC Infect. Dis.20151520910.1186/s12879-015-1032-725943103
  137. M.S. MorganDiagnosis and treatment of Panton-Valentine leukocidin (PVL)-associated staphylococcal pneumoniaInt. J. Antimicrob. Agents20073028929610.1016/j.ijantimicag.2007.04.01917629464
  138. A.S. RossneyA.C. ShoreP.M. MorganM.M. FitzgibbonB. O’ConnellD.C. ColemanThe emergence and importation of diverse genotypes of methicillin-resistant Staphylococcus aureus (MRSA) harboring the Panton-Valentine leukocidin gene (pvl) reveal that pvl is a poor marker for community-acquired MRSA strains in IrelandJ. Clin. Microbiol.2007452554256310.1128/JCM.00245-0717581935
  139. S.M. AbdulgaderA.O. ShittuM.P. NicolM. KabaMolecular epidemiology of Methicillin-resistant Staphylococcus aureus in Africa: A systematic reviewFront. Microbiol.2015634810.3389/fmicb.2015.0034825983721
  140. A.M. BazziA.A. RabaanM.M. FawarahJ.A. Al-TawfiqPrevalence of Panton-Valentine leukocidin-positive methicillin-susceptible Staphylococcus aureus infections in a Saudi Arabian hospitalJ. Infect. Public Health2015836436810.1016/j.jiph.2015.01.01025817805
  141. S. Ohadian MoghadamM.R. PourmandM. MahmoudinH. SadighianMolecular characterization of methicillin-resistant Staphylococcus aureus: Characterization of major clones and emergence of epidemic clones of sequence type (ST) 36 and ST 121 in Tehran, IranFEMS Microbiol. Lett.2015362fnv04310.1093/femsle/fnv04325795589
  142. X. LiuJ. LiangY. JiangB. WangH. YuanL. ZhangY. ZhouH. XuW. ZhouMolecular characteristics of community-acquired methicillin-resistant Staphylococcus aureus strains isolated from outpatients with skin and soft tissue infections in Wuhan, ChinaPathog. Dis.201674ftw02610.1093/femspd/ftw02627060098
  143. M.Z. DavidM.E. AcreeJ.J. SiethD.J. BoxrudG. DobbinsR. LynfieldS. Boyle-VavraR.S. DaumPediatric Staphylococcus aureus isolate genotypes and infections from the dawn of the Community-Associated Methicillin-Resistant S. aureus epidemic era in Chicago, 1994 to 1997J. Clin. Microbiol.2015532486249110.1128/JCM.00096-1526019202
  144. V. PostP. WahlI. UçkayP. OchsnerW. ZimmerliS. CorvecC. LoiezR.G. RichardsF. MoriartyPhenotypic and genotypic characterisation of Staphylococcus aureus causing musculoskeletal infectionsInt. J. Med. Microbiol.201430456557610.1016/j.ijmm.2014.03.00324768432
  145. C. Dunyach-RemyC. Courtais-CoulonC. DeMatteiN. JourdanS. SchuldinerA. SultanC. CarrièreS. AlonsoA. SottoJ.P. LavigneLink between nasal carriage of Staphylococcus aureus and infected diabetic foot ulcers2016Unpublished work
  146. M.H.T. StappersF. HagenP. ReimnitzJ.W. MoutonJ.F. MeisI.C. GyssensDirect molecular versus culture-based assessment of Gram-positive cocci in biopsies of patients with major abscesses and diabetic foot infectionsEur. J. Clin. Microbiol. Infect. Dis.2015341885189210.1007/s10096-015-2428-426143347
  147. A. TristanM. BesH. MeugnierG. LinaB. BozdoganP. CourvalinM.E. ReverdyM.C. EnrightF. VandeneschJ. EtienneGlobal distribution of Panton-Valentine leukocidine positive methicillin-resistant Staphylococcus aureus, 2006Emerg. Infect. Dis.20071359460010.3201/eid1304.06131617553275
  148. K. AntriN. RouzicO. DauwalderI. BoubekriM. BesG. LinaF. VandeneschM. TazirN. Ramdani-BouguessaJ. EtienneHigh prevalence of methicillin-resistant Staphylococcus aureus clone ST80-IV in hospital and community settings in AlgiersClin. Microbiol. Infect.20111752653210.1111/j.1469-0691.2010.03273.x20518793
  149. M. Ben NejmaM. MastouriB. Bel Hadj JradM. NourCharacterization of ST80 Panton-Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus clone in TunisiaDiagn. Microbiol. Infect. Dis.200877202410.1016/j.diagmicrobio.2008.02.01018394845
  150. B. LamyF. LaurentO. GallonF. Doucet-PopulaireJ. EtienneJ.W. DecousserAntibacterial resistance, genes encoding toxins and genetic background among Staphylococcus aureus isolated from community-acquired skin and soft tissue infections in France: A national prospective surveyEur. J. Clin. Microbiol. Infect. Dis.2012311279128410.1007/s10096-011-1441-521997773
  151. F. DuruptL. MayorM. BesM.E. ReverdyF. VandeneschL. ThomasJ. EtiennePrevalence of Staphylococcus aureus toxins and nasal carriage in furuncles and impetigoBr. J. Dermatol.20071571161116710.1111/j.1365-2133.2007.08197.x17916211
  152. B. IssartelA. TristanS. LechevallierF. BruyèreG. LinaB. GarinF. LacassinM. BesF. VandeneschJ. EtienneFrequent carriage of Panton-Valentine leucocidin genes by Staphylococcus aureus isolates from surgically drained abscessesJ. Clin. Microbiol.2005433203320710.1128/JCM.43.7.3203-3207.200516000436
  153. L.A. PuzniakA. QuintanaM. WibleT. BabinchakP.C. McGovernMethicillin-resistant Staphylococcus aureus infection epidemiology and clinical response from tigecycline soft tissue infection trialsDiagn. Microbiol. Infect. Dis.20147926126524725736
  154. E. SennevilleM. BrièreC. NeutN. MessadG. LinaJ.L. RichardA. SottoJ.P. LavigneFrench Study Group on the Diabetic FootFirst report of the predominance of clonal complex 398 Staphylococcus aureus strains in osteomyelitis complicating diabetic foot ulcers: A national French studyClin. Microbiol. Infect.201420O274O27710.1111/1469-0691.1237524118215
  155. F. Alonzo 3rdM.A. BensonJ. ChenR.P. NovickB. ShopsinV.J. TorresStaphylococcus aureus leucocidin ED contributes to systemic infection by targeting neutrophils and promoting bacterial growth in vivoMol. Microbiol.20128342343510.1111/j.1365-2958.2011.07942.x22142035
  156. S.H. FengY.J. ChuP.H. WangX. JunD. MinX.M. LiRisk factors and gene type for infections of MRSA in diabetic foot patients in Tianjin, ChinaInt. J. Low. Extrem. Wounds20131210611210.1177/153473461348999123771611
  157. T.X. NhanR. LeclercqV. CattoirPrevalence of toxin genes in consecutive clinical isolates of Staphylococcus aureus and clinical impactEur. J. Clin. Microbiol. Infect. Dis.20113071972510.1007/s10096-010-1143-421225304
  158. K. BeckerA.W. FriedrichG. LubritzM. WeilertG. PetersC. von EiffPrevalence of genes encoding pyrogenic toxin superantigens and exfoliative toxins among strains of Staphylococcus aureus isolated from blood and nasal specimensJ. Clin. Microbiol.2003411434143910.1128/JCM.41.4.1434-1439.200312682126
  159. J. SilaP. SauerM. KolarComparison of the prevalence of genes coding for enterotoxins, exfoliatins, Panton-Valentine leukocidin and Tsst-1 between methicillin-resistant and methicillin-susceptible isolates of Staphylococcus aureus at the University Hospital in OlomoucBiomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub.200915321521810.5507/bp.2009.03619851435
  160. A.R. SpauldingW. Salgado-PabonP.L. KohlerA.R. HorswillD.Y. LeungP.M. SchlievertStaphylococcal and streptococcal superantigen exotoxinsClin. Microbiol. Rev.20132642244710.1128/CMR.00104-1223824366
  161. B.G. VuC.S. StachW. Salgado-PabonD.J. DiekemaS.E. GardnerP.M. SchlievertSuperantigens of Staphylococcus aureus from patients with diabetic foot ulcersJ. Infect. Dis.20142101920192710.1093/infdis/jiu35024951827
  162. G. LinaG.A. BohachS.P. NairK. HiramatsuE. Jouvin-MarcheR. MariuzzaStandard nomenclature for the superantigens expressed by StaphylococcusJ. Infect. Dis.20041892334233610.1086/42085215181583
  163. R.F. DiegelmannM.C. EvansWound healing: An overview of acute, fibrotic and delayed healingFront. Biosci.2004928328910.2741/118414766366
  164. M.M. DingesP.M. OrwinP.M. SchlievertExotoxins of Staphylococcus aureusClin. Microbiol. Rev.200013163410.1128/CMR.13.1.16-34.200010627489
  165. H.W. LeeS.M. KimJ.M. KimB.M. OhJ.Y. KimH.J. JungH.J. LimB.S. KimW.J. LeeS.J. LeePotential immunoinflammatory role of staphylococcal enterotoxin A in atopic dermatitis: Immunohistopathological analysis and in vitro assayAnn. Dermatol.20132517318010.5021/ad.2013.25.2.17323717008
  166. G.J. WilsonK.S. SeoR.A. CartwrightT. ConnelleyO.N. Chuang-SmithJ.A. MerrimanC.M. GuinaneJ.Y. ParkG.A. BohachP.M. SchlievertA novel core genome-encoded superantigen contributes to lethality of community-associated MRSA necrotizing pneumoniaPLoS Pathog.2011720910.1371/journal.ppat.100227122022262
  167. P. BoquetE. LemichezBacterial virulence factors targeting Rho GTPases: Parasitism or symbiosis?Trends Cell Biol.20031323824610.1016/S0962-8924(03)00037-012742167
  168. L. BoyerA. DoyeM. RolandoG. FlatauP. MunroP. GounonR. ClémentC. PulciniM.R. PopoffA. MettouchiInduction of transient macroapertures in endothelial cells through RhoA inhibition by Staphylococcus aureus factorsJ. Cell Biol.200617380981910.1083/jcb.20050900916754962
  169. E. LemichezM. LecuitX. NassifS. BourdoulousBreaking the wall: Targeting of the endothelium by pathogenic bacteriaNat. Rev. Microbiol.201089310410.1038/nrmicro226920040916
  170. M. RolandoP. MunroC. StefaniP. AubergerG. FlatauE. LemichezInjection of Staphylococcus aureus EDIN by the Bacillus anthracis protective antigen machinery induces vascular permeabilityInfect. Immun.2009773596360110.1128/IAI.00186-0919546197
  171. P. MunroM. BenchetritM.A. NahoriC. StefaniR. ClémentJ.F. MichielsL. LandraudO. DussurgetE. LemichezThe Staphylococcus aureus epidermal cell differentiation inhibitor toxin promotes formation of infection foci in a mouse model of bacteremiaInfect. Immun.2010783404341110.1128/IAI.00319-1020479081
  172. S. InoueM. SugaiY. MurookaS.Y. PaikY.M. HongH. OhgaiH. SuginakaMolecular cloning and sequencing of the epidermal cell differentiation inhibitor gene from Staphylococcus aureusBiochem. Biophys. Res. Commun.199117445946410.1016/0006-291X(91)91438-I1993048
  173. C. WildeK. AktoriesThe Rho-ADP-ribosylating C3 exoenzyme from Clostridium botulinum and related C3-like transferasesToxicon2001391647166010.1016/S0041-0101(01)00152-011595628
  174. G.C. FrankeA. BöckenholtM. SugaiH. RohdeM. AepfelbacherEpidemiology, variable genetic organization and regulation of the EDIN-B toxin in Staphylococcus aureus from bacteraemic patientsMicrobiology201015686087210.1099/mic.0.030304-019875439
  175. T. YamaguchiT. HayashiH. TakamiM. OhnishiT. MurataK. NakayamaK. AsakawaM. OharaH. KomatsuzawaM. SugaiComplete nucleotide sequence of a Staphylococcus aureus exfoliative toxin B plasmid and identification of a novel ADP-ribosyltransferase, EDIN-CInfect. Immun.2001697760777110.1128/IAI.69.12.7760-7771.200111705958
  176. A. CzechT. YamaguchiL. BaderS. LinderK. KaminskiM. SugaiM. AepfelbacherPrevalence of Rho-inactivating epidermal cell differentiation inhibitor toxins in clinical Staphylococcus aureus isolatesJ. Infect. Dis.200118478578810.1086/32298311517442
  177. P. MunroR. ClémentJ.P. LavigneC. PulciniE. LemichezL. LandraudHigh prevalence of edin-C encoding RhoA-targeting toxin in clinical isolates of Staphylococcus aureusEur. J. Clin. Microbiol. Infect. Dis.20113096597210.1007/s10096-011-1181-621311940
The underlying source XML for this text is taken from https://www.ebi.ac.uk/europepmc/webservices/rest/PMC4963842/fullTextXML. The license for the article is Creative Commons Attribution. The main subject has been identified as osteomyelitis.