Download Toxins , , doi. /toxins toxins ISSN www.mdpi.com/journal/toxins

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.