Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Toxins , , doi. /toxins toxins ISSN www.mdpi.com/journal/toxins Review Exfoliative Toxins of Staphylococcus aureus Michal Bukowski , Benedykt Wladyka and Grzegorz Dubin , Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland EMails mbukowgmail.com M.B. wladykabinteria.pl B.W. Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland Author to whom correspondence should be addressed EMail grzegorz.dubinuj.edu.pl Tel. Fax . Received April in revised form May / Accepted May / Published May Abstract Staphylococcus aureus is an important pathogen of humans and livestock. It causes a diverse array of diseases, ranging from relatively harmless localized skin infections to lifethreatening systemic conditions. Among multiple virulence factors, staphylococci secrete several exotoxins directly associated with particular disease symptoms. These include toxic shock syndrome toxin TSST, enterotoxins, and exfoliative toxins ETs. The latter are particularly interesting as the sole agents responsible for staphylococcal scalded skin syndrome SSSS, a disease predominantly affecting infants and characterized by the loss of superficial skin layers, dehydration, and secondary infections. The molecular basis of the clinical symptoms of SSSS is well understood. ETs are serine proteases with high substrate specificity, which selectively recognize and hydrolyze desmosomal proteins in the skin. The fascinating road leading to the discovery of ETs as the agents responsible for SSSS and the characterization of the molecular mechanism of their action, including recent advances in the field, are reviewed in this article. Keywords exfoliative toxin epidermolytic toxin Staphylococcus aureus staphylococcal scalded skin syndrome bullous impetigo OPEN ACCESS Toxins , . Introduction Staphylococcus aureus is a dangerous human pathogen responsible for a wide variety of diseases. Unlike the virulence of many bacteria, which is primarily dependent on the production of a single or limited number of virulence factors to which the observed clinical symptoms can be directly attributed, staphylococci secrete a wide spectrum of diverse extracellular proteins, which render the bacterium virulent. Although these factors, as a group, are essential for staphylococcal virulence, they largely lack the characteristics of typical toxins. They do not act alone, causing specific symptoms, when purified and administered in the absence of the bacterium, and the bacterial virulence is not markedly reduced when only a single factor is knocked out. Nonetheless, some symptoms associated with S. aureus infection are caused by typical toxins, such as toxic shock syndrome toxin TSST, enterotoxins, and exfoliative toxins ETs ,. Exfoliative toxins also known as epidermolytic toxins are particularly interesting virulence factors of S. aureus. These extremely specific serine proteases recognize and cleave desmosomal cadherins only in the superficial layers of the skin, which is directly responsible for the clinical manifestation of staphylococcal scalded skin syndrome SSSS. In this review, the reader is given a brief historic perspective on the fascinating road leading to the discovery of ETs, followed by a description of the present state of the art and the most recent developments in the characterization of the molecular mechanisms underlying ET functions. Finally, directions for further research are proposed. . Staphylococcal Scalded Skin Syndrome SSSS Staphylococcal scalded skin syndrome, also known as Ritters disease, is primarily characterized by skin exfoliation ,. Early SSSS manifests with fever, malaise, lethargy, and poor feeding. These symptoms are followed by an erythematous rash and the formation of large, fragile, fluidfilled blisters. The blisters burst with mechanical action, leaving the affected parts of the body without a protective layer of epidermis ,. Only the skin, but not the mucosa, is involved . SSSS affects large parts of the body and the lesions are often sterile. A localized form of SSSS, restricted to the sites of infection, is recognized as bullous impetigo. Both conditions share the same etiology and differ only in the extent of skin damage. A diagnosis must distinguish SSSS from other skin diseases, such as toxic epidermal necrolysis, epidermolysis bullosa, bullous erythema multiforme, or listeriosis, and thermal or chemical burns, all maintaining the body temperature and protecting the denuded skin to prevent secondary infections and fluid loss are also recommended . This significant delay was caused by the fact that the blister fluid and .of which can manifest with similar symptoms ... SSSS predominantly affects Toxins . Toxin Identity The features of SSSS were first described by Baron Gottfried Ritter von Rittershain in . Mortality among treated children is low and does not exceed . Nonetheless. However. The simplest and most suitable methods of routine diagnosis are PCR for toxinencoding genes or random amplified polymorphic DNA analysis . and resistance is not yet a major problem. but immune system and renal impairment are reported to be susceptibility factors in adults. The higher mortality in adults is explained by the fact that SSSS predominantly occurs with severe underlying disease. Single cases of SSSS have also been reported in adults with no obvious underlying disease .. Problems with the treatment of etbpositive communityassociated MRSA CAMRSA causing SSSS in healthy adults have already been reported in Japan .. Apart from antibiotic treatment. whereas around of MRSA are eta positive . while single outbreaks generally involve around a dozen of cases . The number of fatal cases in adults is much higher. The prevalence of ETA does not differ significantly among methicillinresistant MRSA and methicillinsusceptible MSSA strains.. SSSS is characterized by rare local outbreaks among neonates and sporadic occurrences in adults. aureus was determined by Lyell . it was not until that the relationship between skin exfoliation and S. the French National Center of Staphylococcal Toxins estimated the number of cases at about annually in the s. reaching in some studies . Successful treatment is generally limited to the administration of intravenous antibiotics . For example. resistant strains may become an issue in the future . There are no data concerning the prevalence of SSSS over larger geographical areas. . neonates and infants. Recent reports demonstrated that of MSSA strains carry the eta or etb gene . . reproduced the symptoms of human SSSS . ETproducing strains mainly belong to agr . aureus strains isolated from patients with SSSS. are ETBproducing strains more prevalent than those expressing ETA . Determination of the partial amino acid sequences of the purified toxins has allowed the corresponding genes to be cloned and the toxins to be expressed in heterologous hosts. The toxin was subsequently purified and shown to be a protein of approximately kDa . among many other virulencefactorencoding genes.. Early animal studies showed that blistering can be induced in mice with S.exfoliated regions are often free of cultivable staphylococci. Only in Japan. and these were designated ETA and ETB .. and Africa. These early studies confirmed that a soluble toxin is solely responsible for all the pronounced disease manifestations. A reliable animal model was established. It has been demonstrated that the expression of both eta and etb. The existence of a hypothetical toxin was suggested by Lyell and confirmed by Melish et al.. because the toxin is distributed from distant sites of infection through the bloodstream. USA. It was soon shown that at least two serotypes of ETs exist. Strains producing ETA and ETB show phylogenetic relatedness. It was demonstrated soon thereafter that the presence of bacteria is not necessary because blistering can be induced in model animals by a soluble factor found in the sterile filtrates of bacterial cultures. The orchestrated expression of multiple virulence factors is the key to the success of staphylococcal pathogenesis. and is expressed by more than of toxinproducing strains . In Europe. providing final confirmation that ETs are the sole factors responsible for blister formation in SSSS . who demonstrated the induction of blistering with sterile filtrates of bacterial cultures .. as demonstrated on a representative group of strains using amplified fragment length polymorphism AFLP analysis. ETA is prevalent. in which newborn mice inoculated with toxin producing strains or administered with sterile culture filtrates. The accessory gene regulator agr constitutes one of the major regulatory mechanisms described to date . in . is regulated by agr . Recombinant toxins produced in Escherichia coli retained their activity in a mouse model. the catalytic triad residues of the chymotrypsin family proteases are well conserved in ETs . it was proposed that peptide bond hydrolysis is the mode of the toxin action ..group IV .. because multiple contradictory . early studies provided no direct evidence. but the direct mechanism remained unknown. Epidermal detachment at the stratum granulosum was established by electron microscopy . Importantly. a mutant at the serine of the catalytic triad. multiple studies have tried to demonstrate their anticipated proteolytic activity. Finally. the close resemblance between the toxins and the serine proteases became immediately evident. The esterase activity of ETB was abolished with diisopropylphosphorofluoridate. Toxins . lacked both esterolytic activity and epidermolytic activity when administered subcutaneously into mice . Since the resemblance of ETs to the serine proteases became apparent. . a single biochemical study reported the hydrolysis of isolated peptides alpha and beta melanocytestimulating hormones by the purified toxin . The loss of esterase activity correlated with the loss of toxin effect in a murine model... the molecular mechanism by which ETs induce exfoliation remained a mystery. However. For this reason. The overall picture was not at all consistent in the late s. which provided a useful assay for ETs. Molecular Mechanism of Toxin Activity Since the pioneering work of Melish in the early s.. but it took a decade to irrefutably demonstrate the biologically relevant proteolysis. this proved much harder than initially expected. Concurrently. but its physiological relevance was not demonstrated and the study was not confirmed by other authors at that time. whereas multiple indirect lines of supporting evidence were collected. mainly because the ETs have one of the most limited substrate specificities found among known proteases. constructed in a heterologous expression system. a broadrange serine protease inhibitor . Esterolytic activity a common side activity of serine proteases for the synthetic substrate BocGluOPh was reported . Accordingly. Once the protein nature of ETs was established and the amino acid sequences determined . The amino acid numbering is according to the Protein Data Bank PDB entries EXF ETA and OL glutamylendopeptidase. For instance. respectively. Figure .findings had also been demonstrated. the results of crystallographic experiments suggested that ETs are either proteolytically inactive or that an activation mechanism of some kind must exist. The oxyanion hole constitutes an important part of the catalytic machinery of serine proteases. the oxyanion hole is not preformed in the structure of ETA. A Ribbon representation of the crystal structure of glutamylendopeptidase left and ETA right. The conformation of the catalytic triad was preserved in both toxins . Overall. Exfoliative toxins belong to the chymotrypsin family of serine proteases and are structurally similar to staphylococcal glutamylendopeptidase V protease. this was never convincingly demonstrated .. His. broadrange serine protease inhibitors did not inhibit the exfoliation induced by ETA . but the oxyanion hole was not preformed in either protein Figure . and not in other chymotrypsinlike proteases. blue. stabilizing the negative charge formed on a tetrahedral intermediate during catalysis. and yellow... Therefore. shown in red and light blue. and Ser are depicted in a stick model in red.. until the very beginning of the st century. Although several studies suggested the proteolytic activation of the ETs. and were almost identical to those of the serine proteases of the chymotrypsin family and specifically to that of the glutamicacidspecific proteases. demonstrates that this important part of the catalytic machinery is well developed in the toxin structure. B The superimposition of the catalytic triad residues of glutamylendopeptidase and the corresponding residues of ETA. Toxins . Moreover. . although multiple facts favored this hypothesis. Conversely. as demonstrated by the different orientations of the carbonyl oxygen of the ProGly peptide bond in ETA and the corresponding GlyGly peptide bond in glutamylendopeptidase dashed circle. the reports of different authors concerning the conformation of the oxyanion hole in ETB were conflicting . Except for an additional helix characteristic of the exfoliative toxins and the conformation of some surface loops. The crystal structures of both ETA and ETB were determined. The catalytic triad residues Asp. respectively. no direct evidence of the proteolytic activity of the ETs and especially its association with skin exfoliation was available. the overall fold of both enzymes is almost identical. was responsible. It was immediately speculated that the removal of the atypical Nterminal extension found exclusively in ETs. numbers in parentheses. another theory concerning the mode of toxin action was developed. Nonetheless. other researchers suggested that the results obtained by the groups of Morlock and Choi were the effects of sample contamination with trace amounts of enterotoxins.. aureus or strains of E. proteolytic activity. resulting in the deregulation of the immune response . coli had no mitogenic activity when assessed in human peripheral blood mononuclear cells and murine splenocytes. The same authors also demonstrated that the superantigenicity of commercial preparations of ETs could be attenuated with antibodies directed against enterotoxins A and B .Adding to the overall uncertainty concerning the mechanism of ET activity. demonstrated the mitogenic activity of ETA purified from staphylococcal culture supernatants. later reports have indicated that ETs are truly superantigens and that their mitogenic activity is independent of their proteolytic activity. demonstrating that ETA interacts primarily with T cells and that its mitogenicity is similar to that of enterotoxin A. Soon after. polyclonal proliferation of T cells. demonstrating that recombinant ETA isolated from superantigenfree strains of S. proteins that induce the atypical. The initial results concerning the presumed superantigen activity of ETs were confusing and contradictory. inducing the antigenindependent proliferation of large populations of T cells. Based on information about other staphylococcal toxins. Morlock et al. concurrently with efforts to demonstrate its Toxins . demonstrated that both the wildtype and a . assayed the activity in preparations of murine splenocytes. In a classical way. Early reports by Morlock et al. Vath et al. and Choi et al. demonstrated the elevated expression of a particular variant of the gene encoding the TCR chain in human and murine T cells after their interaction with ETA. Superantigens interact directly with invariant regions of MHCII and TCR. the antigens processed by antigenpresenting cells are exposed as peptides bound to MHCII molecules and selectively induce the proliferation of T cells. The study of Choi et al. which specifically recognize the presented antigen via the Tcell receptor TCR. it was proposed that ETs function as superantigens. . produced mutants with modulated mitogenic activity. Their proteolytic activity seemed directly responsible for skin exfoliation while mitogenic activity. Overall. The superantigen activity of highly purified ETA and ETB was also confirmed by Monday et al. where exfoliation was not induced and therefore the other effects of ETs could be easily distinguished. As a most striking example. The glutamic acid residue . Target of Exfoliative Toxins in the Skin By the mid s. Rago et al. Nonetheless. conditions. both toxins showed milder effects than that of the classic superantigen TSST . who showed the stimulated expression of specific TCR chain genes in human T cells and mouse splenocytes after toxin treatment. the hydrolysis of which would induce skin exfoliation. was probably not directly associated with the primary manifestations of SSSS. Because SSSS lesions show no evidence of Tcell recruitment . observed under particular experimental conditions. aureus strains induced thymidine incorporation in human T lymphocytes .proteolytically inactive mutant toxin purified from superantigenfree S. . it seems that if the ETs are truly superantigens which remains controversial based on considerable contradictory evidence. Other researchers also confirmed the significantly lower mitogenic effect of the ETs compared with those of other superantigens .. the DG mutation in the Dloop of ETA totally abolished its mitogenic activity . The same authors pointed out that ETB had significantly higher pyrogenic activity than ETA in a rabbit model. as yet undermined. it was strongly anticipated that ETs would prove to be proteases whose activity is manifested only under specific. Exclusive specificity of exfoliative toxin A for human desmoglein is dictated by primary interactions at the P specificity pocket and by secondary interactions with tertiary structural elements located away from the site of cleavage. be it physiologically relevant or only Toxins . The only significant missing piece of the puzzle at the time was the target molecule. the presumed superantigenicity of the ETs is probably not involved in the pathogenesis of SSSS. Figure . their mitogenic properties are clearly weaker than those of other staphylococcal superantigenic toxins. A Homology model of domains EC and EC of human desmoglein based on the crystal structure of domains EC and EC of Xenopus laevis Ccadherin PDB ID LW. B Sequence comparison of the EC domain of desmoglein from different species explains the exclusive specificity of ETA for human and mouse desmoglein .. Toxins . QBDI pig.. responsible for the integrity of those celltocell adhesive structures. Calcium ions. The removal of calcium results in domain denaturation and the loss of the capacity of ETs to recognize and . and ETD was demonstrated experimentally both in vitro and in vivo.. QTSF mouse. based mainly on crystallographic studies. The search for the specific target hydrolyzed by ETs was facilitated by studies of autoimmune diseases. Because the clinical manifestations of pemphigus foliaceus are very similar to those of SSSS. are shown as grey spheres. leading to skin blistering and exfoliation. this cleavage is highly dependent on the conformation of Dsg. concerning the substrate specificity of ETs for glutamic acid at the P subsite nomenclature according to Schechter and Berger . The molecular basis of this phenomenon acantholysis is well established and involves autoantibodies directed against desmoglein Dsg . Accordingly. the hydrolysis of Dsg but not of other desmogleins by ETA. These initial findings were followed by the detailed characterization of the mechanisms of Dsg recognition and cleavage . P signifies a residue adjacent to the scissile peptide bond towards the Nterminus of the substrate . It was also demonstrated that unlike classical serine proteases. Conserved amino acid sequences in the EC domains of the analysed species differ primarily in the region recognized by ETA.. which stabilize the desmoglein structure and are essential for cleavage. providing a final explanation of the mechanism of ETinduced epidermolysis . The previous assumptions. and the unfolded protein is not hydrolyzed ..determining the primary interaction at the P site of the enzyme and adjacent to the cleavage site is shown by the arrow red. Pemphigus foliaceus is characterized by disrupted cellular adhesions. Desmoglein is a desmosomal cadherin . QGKQ dog. but does not affect the mucous membranes. it was hypothesized that Dsg is the primary target of ETs. UniProt accession numbers for the desmoglein sequences Q human. Distant sites of secondary interactions are marked in blue according to . The cleavage sites were identified using the recombinant extracellular domain of Dsg . The folding of the extracellular domains of Dsg depends on calcium ions .. Colour coding as in panel A. were directly confirmed .. ETB. The ETs selectively hydrolyze Dsg. an autoimmune disease characterized by the production of autoantibodies directed against Dsg and primarily affecting the mucous membranes . whereas Dsg remains unaffected. except the stratum granulosum. This phenomenon is elegantly explained by the selectivity of desmoglein cleavage and the differential expression of particular desmogleins in different layers of the skin and mucosa. YTIE Figure . Furthermore. Dsg is present in the superficial layers only. Dsg is expressed in all strata of the skin. These conclusions have been further confirmed by studies of pemphigus vulgaris. the exfoliativetoxinmediated hydrolysis of desmoglein Dsg is compensated by desmoglein Dsg. This explains the lack exfoliation of the mucous membranes. which explains the cell detachment and the splitting of the epidermal layers upon the hydrolysis of Dsg. blistering affects only the superficial skin and not the mucosa or deeper skin layers. Dsg is absent in the stratum granulosum. in the deep layers of the skin. The mucous membranes are characterized by different expression patterns of desmogleins. In SSSS. Schematic representation of the desmoglein distribution in A healthy skin and B skin exposed to exfoliative toxin. confirming the previous assumption that the residue determines the specificity of ETs for glutamic acid . In all strata. the disruption of Dsg by ETs is compensated by Dsg and exfoliation only occurs in the stratum granulosum.. The cleavage of Dsg is compensated equally by Dsg in all layers. The mechanisms of this precise recognition and specific cleavage were studied in molecular detail. Therefore. Differential distribution of desmoglein isoforms in the epidermis explains the exfoliativetoxininduced splitting at the stratum granulosum. whereas Dsg is found in all strata . it was demonstrated that the KA mutant of ETA is inactive in a murine model. Figure . whereas Dsg is only expressed in deeper strata . Toxins . Analysis of the ET interaction with domainswapped variants of human desmoglein hDsg and its canine counterpart not hydrolyzed by ETs identified the hDsg region responsible for its recognition and precise protease positioning extracellular domain EC. . Further detailed analysis of point mutants allowed the definition of particular desmoglein residues crucial for the interaction Q. where Dsg is not present Figure .hydrolyze Dsg . It was hypothesized that crossreactive antibodies are responsible for toxin neutralization . The same effects are observed in mouse models. Toxin clearance increases dramatically in the first week after birth.. correlating with the development Toxins . it seems that the mechanism of resistance may differ in its details between humans and mice. .. no increased susceptibility to purified toxin was observed . as far as the involvement of the immune system is concerned. Studies in adult mice confirmed that treatment with immunosuppressants increased their susceptibility to ETsproducing S. unlike in mice. inferred from the known susceptibility factors in adults. It is well established that the impairment of the immune system. However. including pharmacological immunosuppression in autoimmune diseases. lymphoma chemotherapy .. It remains to be determined whether the impairment of renal clearance or the deregulation of the immune response is primarily responsible for toxin susceptibility in human subjects with underlying kidney disease. Severe kidney disease is another susceptibility factor for SSSS in adults. as mentioned above. no difference in the time course of the development of toxin resistance or the level of resistance in adults was observed . Toxin Susceptibility In humans. Therefore. aureus strains. in which the animals are susceptible only until day seven of life . of resistance . and that the overall condition of the immune system has no effect on toxin susceptibility. are risk factors for both SSSS and bullous impetigo in adult human subjects. Studies in thymectomized mice demonstrated that the humoral response was not involved in toxin resistance. Renal impairment results in the deregulation of the immune responses . which may further increase the susceptibility to either the toxin itself or simply pathogen infection. In this animal model. the overall condition of the immune system is also important. At the same time. The search for a likely explanation followed two paths.. it seems that in human subjects. Data are available that demonstrate that the toxin susceptibility of mice is dictated solely by the rate of its clearance from the bloodstream. SSSS primarily affects neonates. and AIDS . it seems that at least some toxins are involved not only in SSSS and bullous impetigo but also in other cutaneous infections. aureus produce mainly ETA and ETB . including SHETA. but only ExhA and ExhC also cause it in neonatal mice .. Humaninfecting strains of S. chromogenes have also been shown to produce ExhB . the relevant data are too few to allow final conclusions to be drawn. chicks.. SHETB . and ExhD . It has been demonstrated that. novel serotypes of ETs . This toxin can affect horses. The production of ETC was demonstrated in an S. This toxin induces exfoliation in a mouse model .. respectively . ETDproducing strains are mainly isolated from furuncles or cutaneous abscesses. the genes of which are chromosome and plasmid located. ExhA. All these toxins induce exfoliation in human but also in a mouse model . aureus and other species of staphylococci. produces multiple ETs.. ExhC. However. SpeciesSpecific Diversity of ETs Since the discovery of exfoliative toxins ETA and ETB . Nonetheless. but also induces exfoliation in chicks . encoded by a gene located within a . and . aureus strain isolated from a horse with phlegmon. together with the host specificity of particular strains or species of the pathogen. Staphylococcus chromogenes produces the SCET exfoliative toxin . Canine strains of S. All four Exh toxins cause exfoliation in pigs.kb pathogenicity island chromosomal site encoding virulenceassociated factors. Some pig isolates of S.. ExhB. which is implicated in the pathogenesis of exudative epidermitis in adult pigs.. the toxins produced are also specific for various host organisms. whereas the SHETBencoding gene is located on a plasmid . Overall. multiple homologous toxins have been isolated from S. it is anticipated that with more detailed studies... of isolates. Staphylococcus hyicus. ETD toxin. Both toxins trigger exfoliation in piglets and chicks but not in mice . but is less common than the other two toxins . respectively ... The SHETAencoding gene is chromosomally located. a species commonly isolated from pigs. and suckling mice . pseudintermedius produce a serotype of ET designated EXI. and not from SSSS . has also been described . but partially overlapping. in the light of multiple conflicting reports. a phenomenon associated with their adaptation to speciesspecific differences in the structures of desmogleins. The etb gene is plasmid encoded and is therefore also likely to transfer horizontally. . the destruction of the epidermal barrier facilitates the efficient progression of the infection. The target protein. The toxin can spread with the bloodstream and therefore not all lesions are infected. These will be characterized by slightly divergent. The toxins are serine proteases with very limited substrate specificity. is recognized both through an interaction at the classical P site and via additional features in the tertiary structure. substantiated with basic biochemical . First. the . Concluding Remarks Most pieces of the exfoliative toxins puzzle are currently in place. It has been demonstrated that the gene encoding ETA is located on an integrated . Macroscopically. Apart from this clear and seemingly complete picture. This feature allows the horizontal transfer and shuffling of genes between strains. several issues await further clarification. located away from the site of hydrolysis. their locations on mobile genetic elements. accelerating strain adaptation and allowing host jumping. Toxins . enterotoxins in both an animal model and isolated lymphocytes. desmoglein . the primary symptom of SSSS.will be discovered in different species of staphylococci. Overall.kb phage designated ETA and can transfer horizontally . A careful. the true nature of the superantigenic properties of ETs and their relationship to their pathogenesis remain to be determined. this manifests as epidermal detachment. ranges of affected species. Apart from the etb gene. Such adaptations are associated with yet another significant feature shared by ETs and many other staphylococcal virulence factors.kb pETB plasmid carries genes encoding other virulence factors . quantitative analysis that compares the effects of ETs and those of classical staphylococcal superantigens TSST. The cleavage of Dsg results in the destruction of desmosomal cellcell attachments in a superficial layer of the skin. Overall. A more detailed investigation of the interaction between ETs and Dsg may facilitate the development of such a system. It is well established that in humans. If the importance of these secondary interactions in the substrate recognition and the high substrate specificity of the exfoliative toxins is confirmed. and the reasons for this are still obscure. it seems that the mechanism of resistance differs in its details between humans and mice. SSSS mainly affects newborn children rather than adults. the overall proficiency of the immune system is responsible because immunosuppression is a major risk factor for SSSS in adults. Overall. which are directly relevant to the role of ETs in staphylococcal physiology. Nonetheless. Many such infections are characterized by extensive tissue damage. Apart from the issues discussed above. demonstrating that thymectomized adult mice are resistant to ETs . clearly contradictory findings have been published.studies of TCR and MHC binding by the ETs. question concerning ETs regards their presumed roles in staphylococcal skin infections other than SSSS and bullous impetigo. Another interesting. ETs might prove ideal tools for processing appropriately constructed recombinant fusion proteins. It has been hypothesized that crossreactive antibodies developed in childhood neutralize ETs before they reach the superficial skin layers. would convincingly address these issues. and such a study is eagerly awaited. Currently available data suggest that ETs recognize their substrates by both the classic P site interaction and significant secondary interactions involving the tertiary structural features of the desmoglein ligand. as yet unanswered. aside of other known factors. Second. and this issue requires further clarification. it would be very exciting to define the molecular interaction between ETs and Dsg in atomic detail. the mechanisms underlying the substrate recognition by these proteases are most interesting. we believe that although the main issues concerning ET activity are already well . This presumed effect has not yet been studied beyond the fact that ETDproducing strains are often isolated from lesions other than SSSS . Because such secondary interactions are uncommon among serine proteases. may well be caused by the localized action of ETs. which. . Rev.. P..M. Rapid identification by polymerase chain reaction of staphylococcal exfoliative toxin serotype A and B genes.R. . Raymond. Suzuki. . J. Staphylococcal scalded skin syndrome in a neonate. K. Microbiol. Pollard.M. .. S.S.. F. Lochrie.. Bingen.M.. Eur. R.. . Dinges. M. C. and G. Hardwick... J. Clin. Proft. Biol. Evans. S. Schlievert.. Desmosomes and disease pemphigus and bullous impetigo. Gendrel.R.D. D.E. Y. . .. . . Toxins . pp. . Sakurai. Influence of immune and renal factors. G. . Ladhani.L.. Rev. . Opin. . E. . .. D.. Brahimi. . A clinical review illustrated with a new case.P. Lepercq. J. Mirror Midwives J. In Microbial Toxins Current Research and Future Trends.R. Curr. . Cell. Acad.. E. exfoliative toxins. M.. Clin. Hanakawa.established.M. and biochemical aspects of the exfoliative toxins causing staphylococcal scaldedskin syndrome. References and Notes .R. . M. N. . E.. Immunol.M. . Dermatol. Clinical. Sharpe. Piemont. . . . Caister Academic Press Norfolk. . Toxic epidermal necrolysis. Machida. respectively. Parry. UK. .W. Detection of genes for enterotoxins. Poston. Tyler. . A.. table of contents. Payne.. . .. Staphylococcal scalded skin syndrome in adults. .. Br. Ashton. J. Exotoxins of Staphylococcus aureus. C.W. J. A. H.. . Lyell. K. B. . Microbiol. Amagai. . Clin. N. Cribier. Infect. Grosshans.. Dermatol. S. Staphylococcal scalded skin syndrome in an adult. S.M. . D.. Acknowledgements We apologize to all authors whose contributions were not cited because of space limitations or our unintentional omission. Y. This work was supported in part by grants N N and N N from the Polish Ministry of Science and Higher Education to B. . Badoual. and toxic shock syndrome toxin in Staphylococcus aureus by the polymerase chain reaction.. J.P. W. J. the system is worth further attention because interesting and meaningful results should be achieved with such studies. Ewan. Microbiol. Clin. T. Microbiol.D. P. J. Am. Rozee. Dis.. Johnson. Orwin. Joannou.. Microbiol. Stanley. microbial. . Nurs. Bergeret. . . . . . .. J. So. Gnehm.W.S. Allman. . . Clin. Clonal association of Staphylococcus aureus causing bullous impetigo and the emergence of new methicillinresistant clonal groups in Kansai district in Japan. A. Toxins ... . Hayashi. Wiley.. G.A. L. Naas. B. Die exfoliative dermatitis jungener senglinge. exfoliatins. . J. Opal. J. M.. .. Vaudaux. . . L. . S.. Sauer. . Comparison of the prevalence of genes coding for enterotoxins. H.. Fresco. Olomouc. J. Infect. Melish. Glasgow. JohnsonWinegar. H. Komatsuzawa. Microbiol. Gervaix. M. Nishijima. C. Watanabe. U.. C. . C. Staphylococcal scalded skin syndrome the expanded clinical syndrome. Kolar. O. .E. Yamaguchi. J. S. .. Y. Kind. T. Kinderheilkd . Von Rittershain.. Microbiol. ..G. M. P. J.. Pap. B. . Francois. Z.. N. G. Staphylococcal scalded skin syndrome in two immunocompetent adults caused by exfoliatin Bproducing Staphylococcus aureus. Microbiol. P. El Helali.. Noguchi. Nordmann.. Heininger. . N.. H. J. . .. T. Megevand.. Hosp.P. Palacky. Cross. . . Giovangrandi. C. . Gemmell. Nosocomial outbreak of staphylococcal scalded skin syndrome in neonates epidemiological investigation and control. M.R. A. A. Infect. Hitzler. M. M. . Carbonne. . . Staphylococcal scalded skin syndrome. S.... Norden. ... Dis. Aepfelbacher.. Schrenzel. J. M. article online in advance of print. Terajima. Sasatsu. Biomed. Infect.. Pediatr. Glasgow. Sugai. Aebi. Fac.D. T. Nakaminami.. Med. Czech Repub. . S... Yokota. Antimicrobial agent of susceptibilities and antiseptic resistance gene distribution among methicillinresistant Staphylococcus aureus isolates from patients with impetigo and staphylococcal scalded skin syndrome. Med. . Berger.. P.. A.. Rogolsky. I. Fortineau.M.. N. Clin. . H. . Univ. C. Ohara. Molecular epidemiology of the nasal colonization by methicillinsusceptible Staphylococcus aureus in Swiss children. Kerneis.. H. .. P.. toxinmediated exfoliation in a healthy adult. Infect. .... Staphylococcal scalded skin syndrome potentiation by immunosuppression in mice.. Astagneau.B. .A. . pantonvalentine leukocidin and tsst between methicillinresistant and methicillinsusceptible isolates of Staphylococcus aureus at the university hospital in olomouc. M. C. Immun. . Microbiol. Kurokawa. Sila. Renzi.. . Y.. J. Clin. Sakurai. J.M. Toxic epidermal necrolysis produced by an extracellular product of Staphylococcus aureus.E. Sakurai. purification. . Infect. Med. New type of exfoliatin obtained from staphylococcal strains. . Sarai.D. Infect.P. . Metzger. .. M. Kapral.A. Infect. I. Infect.. Med. L...P. . Molecular and serological differentiation of staphylococcal exfoliative toxin synthesized under chromosomal and plasmid control.. R. Arbuthnott. . .. .. Lyell. Purification of exfoliatin produced by Staphylococcus aureus of bacteriophage group and its physicochemical properties.. . I. . . Sarai. Two serotypes of exfoliatin and their distribution in . A. A. J. J. Microbiologica . .. Wiley. . Engl. Immun.. . Melish. . de Azavedo.. Sarai. K. isolated from patients with impetigo and Ritters disease. S. Schaal. . . . .D. M.. Br. Wuepper. .. Glasgow. . J. Dis. Dermatol.. Billcliffe. . Rogolsky. A review of toxic epidermal necrolysis in Britain. . Turner. . Immun. Futaki. . . . Kent. F.P.A. B. Br.. Glasgow.D..A. Immun. . Dermatol. Kondo. Immun. . Kondo. Kondo.F. J. J. L. Arbuthnott. . C. . J. Miller. M. Sakurai. N. Spero.E. Adesiyun. M. . J. Infect. Infect. .. Isoelectric focusing studies of staphylococcal epidermolytic toxin. The staphylococcal scaldedskin syndrome isolation and partial characterization of the exfoliative toxin. Arbuthnott. The staphylococcal scaldedskin syndrome. A. S. . I. . .. S. A. Product of Staphylococcus aureus responsible for the scaldedskin syndrome. . Gemmell. J.. Y. S. . .. . . FEBS Lett.L. belonging to phage groups other than group II..P. . Toxins . Lyell.. . W. M. .G. L. Y. Purification and characterization of a staphylococcal epidermolytic toxin. . J. . B. J. . Production. Immun. Melish. Johnson. Infect. Y. Exfoliative toxin production by Staphylococcus aureus strains isolated from animals and human beings in Nigeria.D. and chemical characterization of Staphylococcus aureus exfoliative toxin. Thompson.. Lenz. . Microbiol. Dimond..A. W. Prevalence of epidermolytic toxin in clinical isolates of Staphylococcus aureus. Immun. . . . K. .B. J. Thioulouse... J.J.D. Arnaud. J. Exfoliatinproducing strains define a fourth agr specificity group in Staphylococcus aureus. T. Stewart. Meugnier..... . C.. Jarraud.. Lyon. Ohnishi.. J. ..J. Vandenesch. Johnson. . L. . Nakayama. and human disease. . S. . . T. F.. B. Osmotic and growthphase dependent regulation of the eta gene of Staphylococcus aureus a role for DNA supercoiling. Gen.J. F. Etienne.A. R. . Site of action of exfoliative toxin in the staphylococcal scaledskin syndrome..Y.J.S.. C. A. . T. L. Novick. Etienne. .J.. . . Vandenesch. Mol.T. Clin. J. . Bacteriol.. S. T. R.. F. ... Figueiredo. .. Park..S. . K. Lyon. . O. A.. Hayashi. Lillibridge. Bacteriol. Microbiol. C.D... Sequence of the exfoliative toxin B gene of Staphylococcus aureus. Jarraud.W. K. .. . L..E. C.B. T. . Yamaguchi.P. Takami. . . . P. Novick. G. . Yamasaki. M. Lina.W. Foster.. Glasgow. Nucleotide sequence of the epidermolytic toxin A gene of Staphylococcus aureus. Pathog. Peptides .staphylococcal strains isolated from patients with scalded skin syndrome. . Iandolo.. H. Asakawa. . G. ..W. Bacteriol. J.. Genet. C.. F. Melish. Schmidt... . J. . Foster. A. T.. agr groups alleles. Yamaguchi. Bacteriol.M. . Mougel. OToole.. G. de Cicco.. Infect.. L. .. . J. Spero. Foster. Pediatrics . Etienne. ChapuisCellier. M. Iandolo.. Sugai. . . M. Clin. Forey. G.P. J. JohnsonWinegar. virulence factors.. Infect. J. Gerard.J. F. X. ... J. Immun.. T.P. Muir. Molecular cloning and expression of the epidermolytic toxin A gene of Staphylococcus aureus. J.J. Microbiol. Sheehan. Immun. . J.. Lee. Lina. Spero. . Murata. J. H. B. G.. . Peptide signaling in Staphylococcus aureus and other Grampositive bacteria. . Purification and characterization of different types of exfoliative toxin from Staphylococcus aureus.. . Microb. . Clinical manifestations of staphylococcal scaldedskin syndrome depend on serotypes of exfoliative toxins. Jackson. . Sequence determination and comparison of the exfoliative toxin A and toxin B genes from Staphylococcus aureus. T. S. Vandenesch. Cades. Nesme.J. M. . Dorman.. J. . OToole.J. Relationships between Staphylococcus aureus genetic background. . . . P. . Vath...J.. . J. Komatsuzawa. . Earhart. Schlievert. Saldanha... Saldanha. Iandolo. J. P. Protein Eng. C. Schlievert. C. Lett. . D. Vath. C. The structure of the superantigen exfoliative toxin A suggests a novel regulation as a serine protease. M. Cavarelli. Jhoti. . B.H. Ohlendorf. I...M.. R. Smith. C. L. Mourey.A. G.C. . Rifai... . T. Immun. A resolution. Chevrier. M.V. T. A. D.J.J. Ohlendorf. Bailey. Immun.. . R. Foster.. Rago.. .. . Y. J. Prevost... Redpath. . Infect. R. J. D. . G..A.. The esterolytic activity of epidermolytic toxins.. .. EDINC. Functional evidence that the Ser residue of staphylococcal exfoliative toxin A is essential for biological activity.. G. P. H... . H.V.B. Structure . . L.and betamelanocytestimulating hormones. Bilwes. Bohach. J. D. Chaix. J. Rago. S. . Infect.M. Bohach.. The role of the serine protease active site in the mode of action of epidermolytic toxin of Staphylococcus aureus. The reactive serine residue of epidermolytic toxin A. Piemont. DNA sequencing of the eta gene coding for staphylococcal exfoliative toxin serotype A. Garratt. . M. Biochem. . Barbosa. Moulinier. Suzuki. . . Toxins . Bailey. Staphylococcal exfoliative toxins cleave alpha. . G.A.. D. J.. .M.. . Delagoutte.L.W. Sugai. Piemont. Tripp. Redpath. Moras.H. Monie.P. C.J.. . Ohlendorf.. . FEMS Microbiol. . . . . at .. ..Ohara. Evans. Rifai. T. FEBS Lett. G. J. B. Y.. H. M. S.. The . Sakurai.. S. Biochem. . .. Dancer.M. P.A. W. J. M. The structure of Staphylococcus aureus epidermolytic toxin A.B. Gen. Bourguet. . Complete nucleotide sequence of a Staphylococcus aureus exfoliative toxin B plasmid and identification of a novel ADPribosyltransferase. . . M. Earhart. Prevost. Immun. Microbiol... J. S.H..J. Infect..D. Kondo. an atypic serine protease. Bailey. Vath. . The epidermolytic toxins are serine proteases. Biochemistry . . Schlievert.J.M. .J... . G.M.. G. Pt . Kim. Novel features of serine protease active sites and specificity pockets sequence analysis and modelling studies of glutamatespecific endopeptidases and epidermolytic toxins. .H.A. . Garratt.. M. P. . B.D. Monday. . Med. I..V.. Fleischer. L. .K. . Superantigen. J. Immunol. Immunol. Nishifuji. Kappler. Hanakawa.. . Stanley. . Jr. J. . Spero. . . Biochemistry . . Infect. J. Beutner. Bohach.. B. Protein Sci. C.R. Sams. Ninomiya..J. J.R..W. C. Sci. Davis.. . J. Y. J. .C. Mutational analysis of the superantigen staphylococcal exfoliative toxin A ETA.. W.. Purification of protease from a mixture of exfoliative toxin and newbornmouse epidermis. G. Unique superantigen activity of staphylococcal exfoliative toxins. Deobald. USA .. . S.. Staphylococcal exfoliative toxins quotmolecular scissorsquot of bacteria that attack the cutaneous defense barrier in mammals. G. A.. . . P. Y.M. Recombinant epidermolytic exfoliative toxin A of Staphylococcus aureus is not a superantigen. Jordon. Infect. J.H. . Iandolo.. P. D.. Sci. Lin.. .M. H. J. Collins. .. Johnson.D. G. C.C.M.A. . .V. A. L. Mitogenic activity of staphylococcal protein A is due to contaminating staphylococcal enterotoxins.M. Sugai... B.. . J. Negative complement immunofluorescence in pemphigus. .. Choi. M. J. . J. Plano. Papageorgiou....A. Ito. J.. . E. R. . Proc. . Structural similarities and differences in Staphylococcus aureus exfoliative toxins A and B as revealed by their crystal structures. B. C. Leprol... . Interaction of Staphylococcus aureus toxin quotsuperantigensquot with human T cells. Diaz. . Amagai.A.J. Enzymatic and molecular characteristics of the efficiency and specificity of exfoliative toxin cleavage of desmoglein .. Callahan. . .A. L.R. Toxins . G. Y.. Acad. Indian J. W. J.. N. D. Rago. Schlievert. Immunol. . Takiuchi.M. Koulu. . Vath. Vath. Acharya.H. Chem. L. Herron. K.. C. D. M. Invest. Amagai. Bohach.. Dermatol. . Rago. .. Venereol. . Schlievert. Methods . Stanley.J. Biol. . Natl. Fleischer. Immun. Dermatol. Marrack. Dermatol. K.R..crystal structure of exfoliative toxin B a superantigen with enzymatic activity. Chapes... Immunol. . . Immun. Monie.. . Schrezenmeier. . .. . . Ferens.. .. J.M. Distinction between epidermal antigens binding pemphigus . . Bailey. Vaishnani. S... M. Schechter. Morlock.E. . P. Gahr. . Kotzin. Ohlendorf. Mitogenic activity of staphylococcal exfoliative toxin. J.. Thivolet. Microbiol. . Ohlendorf.H. Nishifuji. . G.R. K. W.. . H. .. . Nishifuji. . M. M.R. J. K.. M. Andl. . Rev. C. C. ... Selwood. Dermatol. Amagai. J. Komatsuzawa. . . . . M. T. Sugai. Huen. I. L. .. Green. . M. Matsuyoshi.. Ewing. . Clin. M. Med. . Collins.I. Hanakawa. Lin.. Immun. Marcozzi. Sullivan. M. Eyre. J.R. T. Amagai.. N. Fudaba. . J. A. Woo.. M. Aepfelbacher. R.R. Yamaguchi. . . R. A. .. . Schechter. J.. . Yamaguchi. King. S. . Invest... Nishifuji. Wang. D. Med.H. M. Angst. Cell Sci. Nat. Biochem. N. . ... Berger. Res.. . Cell Biol. Schechter.R. Plano.R. Calciumdependent conformation of desmoglein is required for its cleavage by exfoliative toxin.. A. T.. Nishifuji. Clin. and EDINB. Lin. Schechter. C... J. Y.. Sasaki. Ohara. Hanakawa.H. Biophys. Nat. Human autoantibodies against a desmosomal protein complex with a calciumsensitive epitope are characteristic of pemphigus foliaceus patients. Li.. Sugai. J.. On the size of the active site in proteases. C. Takata. . Y.. ETD. . . Y. Woischnik. Toxins .. Mol.. . L. Identification of the Staphylococcus aureus etd pathogenicity island which encodes a novel exfoliative toxin. Working out the strength and flexibility of desmosomes.. .. . Invest. Z. J. K.. Stanley.. Garza.. A. . Sugai. Stanley.M. Stanley. Stanley. . Exp. Y. B. J. .J. Amagai. J.A.. M..I. B. J. Cell Sci. Arnemann.S. J.. T. Fudaba. Amagai.. . N. K.R.. Adkins. . .C. Dermatol. Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome. Papain. J..D.. Commun. Stratificationrelated expression of isoforms of the desmosomal cadherins in human epidermis.. Magee. Invest. Staphylococcal exfoliative toxin B specifically cleaves desmoglein . Invest.M..W. K. . . . I. . M. Pt . .vulgaris and pemphigus foliaceus autoantibodies. Toxin in bullous impetigo and staphylococcal scaldedskin syndrome targets desmoglein . Infect. The cadherin superfamily diversity in form and function.. . T. ... K.. Magee. Getsios.M.. Stanley. I. H. . Hanakawa. Yamaguchi. R.. Toxin levels in serum . Y. Buxton. C. . S. F. A. Immun. Waugh.. Dermatol. Acad. OReilly.M. M. Foster.J. Wuthrich. J. . M. Arbuthnott. II. Melish. M. Petzelbauer. Epidermolyic toxin in staphylococcal infection toxin levels and host response.. KlarMohamad. . A. K. . Med. Production and cytokinemediated regulation of monocyte chemoattractant protein by human proximal tubular epithelial cells. Friedrich. M.. Yoshinaga. G. J. Sprouse. P. . M. MathieuSerra.. . .. Hautarzt . Renal tubular epithelial expression of the costimulatory molecule BRP inducible costimulator ligand. Dagg. K.. . .. .. .. . .H. Suppl. B. Neuweiler. Staphylococcal scalded skin syndrome in a homosexual adult.S. .correlate with the development of staphylococcal scalded skin syndrome in a murine model. . Relationship between susceptibility and immune . M. . J. C. . The staphylococcal scalded skin syndrome in two elderly immunocompromised patients. Fritsch. Le Hir. Mittermayer. Wahl..A. Gerritsen. Bishop. Elias. . van Es. G. Kondo. H.W. Richard. Dougan.A. P. J.S.M. .F.. Staphylococcal scalded skin syndrome in adults with acute kidney failure. J. . Hall.E.. J. Clin.. Daha. J. Murata.. . J.. S. .S. . Prevalence of genes encoding pyrogenic toxin superantigens and exfoliative toxins among strains of Staphylococcus aureus isolated from blood and nasal specimens. K. Wolff. Peters. Prodjosudjadi. . Von Eiff. R. ..M. . . . Expression of HLA antigens on renal tubular cells in culture. Br. . W. R.. Microbiol. . Schoop.. Microbiol. MacKie. Bruijn.. J. P. R. Am.P. Transplantation . G.R. I. . Sakurai... Soc. Weilert.. Chen. Bakteriol.K. J. S. .P. . . Bilic.. Invest. . G. M. Machida. Stuckey. Ed. J.. T. J. L. .. Kidney Int...A. R. Staphylococcal toxic epidermal necrolysis species and tissue susceptibility and resistance. Ikawa. N.. Am. A. P. Res. Zentralbl. .. Gen. Infect. Becker. ... K. Effect of increased HLA antigen expression on tubular cell stimulation of lymphocyte activation and on their vulnerability to cellmediated lysis... Clin.. Lubritz.A. Plasmids in epidermolytic strains of Staphylococcus aureus.. G. S. M. Nephrol. Konrad.. Dermatol. OKeefe. . . . Gerritsma. . L. .. H. M.. .. K.O. . R. H. J. F. H. T. Distribution of the exfoliative toxin D gene in clinical Staphylococcus aureus isolates in France. H. Nakamura.. Vet.. N.. . Sato. . T. Toxins . . H. . Etienne.. L. New exfoliative toxin produced by a plasmidcarrying strain of Staphylococcus hyicus. . G. Sato. Murata. Y... O. C. C. Sato. Microbiol... . Bacteriol. J. Terauchi. H. Watanabe. . Aizawa. Aizawa. T. Tanabe.. Kuramoto. Sato. A.. Kuramoto. ..response to staphylococcal exfoliative toxin A in mammalian species. Infect. ... K.. T.. Yamaguchi. N. . N. . Sato. Shimizu. Hasegawa. P. Microbiol. Saito.. Maehara. Watanabe. . Infect. . . K. H.. Saito. Immun. Hashimoto. Kawano. Microbiol. A new type of staphylococcal exfoliative toxin from a Staphylococcus aureus strain isolated from a horse with phlegmon. Maehara. Differentiation and distribution of three types of exfoliative toxin produced by Staphylococcus hyicus from pigs with exudative epidermitis. T. H. .. . Maehara. M. Ahrens. Clin.. A. . .. Tanabe. . . Danbara. C. T. . . Chromosomal and extrachromosomal synthesis of exfoliative toxin from Staphylococcus hyicus. Immun. Vandenesch. . Tanaka. Aizawa. and D. .. Lina.. Microbiol. T... Andresen. Andresen. hyicus. H. Cloning and sequence analysis of genes encoding Staphylococcus hyicus exfoliative toxin types A. A... Ohtake.. . Murata. Saito. A.. B. Isolation of exfoliative toxin from Staphylococcus intermedius and its local toxicity in dogs. T. Ohtake. Vet... . Y. Infect. . Med. C. Y. . M. J.. Bes.O.. H. . J. . .. FEMS Immunol. Matsumori.. H. Microbiol. . Tanabe. . Higuchi. Sato. hyicus and its exfoliative activity in the piglet. Susceptibility of various animals and cultured cells to exfoliative toxin produced by Staphylococcus hyicus subsp. Vet. Yamasaki. .. Microbiol. M.. Teruya. Saito.. . M. Bacteriol. Isolation of exfoliative toxin from Staphylococcus hyicus subsp. Tristan. . Saito. Immunol. Sugai.. H. T. Yamaguchi. .. .. M. S.. Daugaard. Med. Mol. . .. Yamaguchi. .. Lab. Makino. Immunol. T. Hanner. Y. Hayashi..... J. Di. Takami. Nakayama. N. S. S... .org/licenses/by/. Henics. . .. Maehara. S. Sato. Nakasone. K. Lett.. Purification and characterization of a novel Staphylococcus chromogenes exfoliative toxin. A. K. Sunaga. Diagn. . Kato. Vet. . .. Terauchi. Microbiol. Dryla. Comparison of antibody repertoires against Staphylococcus aureus in healthy individuals and in acutely infected patients. T.s Vet. W. . . V. A. T... Gelbmann. Ahrens. D. Hirose. Abe. R. . Clin. L.. S. M. Public Health . SakuraiKomada. Exudative epidermitis in pigs caused by toxigenic Staphylococcus chromogenes. . Andresen.. H. Vet. by the authors. licensee MDPI. .. . K. I.. . Kocsis. K... Yamada. N.. . Bettinger. BilleHansen. E.. P.. Ohnishi./. FEMS Microbiol. Nagy. Kustos. T. Microbiol. Kurokawa. Meinke.. Basel.. M.O. H. F. Switzerland... T.. Sugai. This article is an Open Access article distributed under the terms and conditions of the Creative Commons Attribution license http//creativecommons. L. E. . B. Infect.. Phage conversion of exfoliative toxin A production in Staphylococcus aureus. FutagawaSaito... . Identification of first exfoliative toxin in Staphylococcus pseudintermedius. Fukuyasu. BaThein. B. Moromizato. Komatsuzawa. Prustomersky. H.