Bacaan POOl2104.pdf

Please citeStaphyloco

ARTICLE IN PRESSG ModelIJMM 50775 19International Journal of Medical Microbiology xxx (2013) xxx xxx

Contents lists available at ScienceDirect

International Journal of Medical Microbiology

jo ur nal homepage: www.elsev ier .co

Mini Review

Hostpathogen interactions in epidermolysis bulcoloniz

Magdale l F.Q1Jan Maara Department o , HanzThe Netherlandb Department o lein 1,Netherlands

a r t i c l

Article history:Available onlin

Keywords:Epidermolysis bullosaStaphylococcus aureusWoundColonization

iseaseteria

We therefore determined the S. aureus colonization rates in EB patients from the Netherlands by col-lecting swabs from their anterior nares, throats and wounds. Within a period of 2 years, more than90% of the sampled chronic wounds of EB patients were found to be colonized by S. aureus. Moleculartyping revealed that EB patients were not colonized by a single S. aureus type. Rather the S. aureus pop-ulation structure in the sampled EB patients mirrored the local S. aureus population structure within theNetherlands. Furthermore, multiple types of S. aureus were found in close proximity to each other within

Staphylocopathogen?

StaphyloQ2found in th(Wertheim frequent cainclude thenal tract, va2010). The established1997). Howrupted, or become a d

CorresponGroningen, UnEB80, 9700 RBfax: +31 50 36

E-mail add

1438-4221/$ http://dx.doi.o

1

2

3

4

5

67

89

10

11

12

13

14

151617

1819

20

21

22

23

24

25

26

27

28

29

30

31

32 this article in press as: van der Kooi-Pol, M.M., et al., Hostpathogen interactions in epidermolysis bullosa patients colonized withccus aureus. Int. J. Med. Microbiol. (2013), http://dx.doi.org/10.1016/j.ijmm.2013.11.012

individual chronic wounds, indicating that these S. aureus types are not mutually exclusive. Over time,strong uctuations in the S. aureus types sampled from individual EB patients were observed. This highexposure to different S. aureus types is apparently reected by high plasma levels of antistaphylococcalIgGs, especially in patients carrying multiple S. aureus types. It remains to be determined to what extentthis strong immune response protects EB patients against serious staphylococcal infections. Lastly, fur-ther research is needed to dene the impact of staphylococcal colonization of chronic wounds on thedevelopment, exacerbation and healing of such wounds in patients with EB.

2013 Published by Elsevier GmbH.

ccus aureus harmless commensal or dangerous

coccus aureus is a Gram-positive bacterium frequentlye nasal cavity of humans and several animal specieset al., 2005). In humans, the anterior nares are the mostrriage sites for S. aureus. Other known carriage sites

skin, perineum, pharynx as well as the gastrointesti-gina and axillae (Mermel et al., 2011; Lauderdale et al.,colonization rate in the healthy human population is

at about 30% (Wertheim et al., 2005; Kluytmans et al.,ever, if the primary barrier function of the skin is dis-if the immune system is compromised, S. aureus canangerous pathogen that has the potential to invade

ding author at: Department of Medical Microbiology, University ofiversity Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, HPC

Groningen, The Netherlands. Tel.: +31 50 3615187;19105.ress: [email protected] (J.M. van Dijl).

almost all tissues and organs causing a broad range of diseases(Lowy, 1998). These can vary from mild skin infections, such asimpetigo, to life-threatening systemic infections (e.g. pneumonia,meningitis and sepsis) (Zervos et al., 2012; Forsblom et al., 2011;Aguilar et al., 2010; Corrah et al., 2011). Not only the diseases thatthis pathogen can cause are alarming, but also its high propensity toacquire resistance to antibiotics (Lowy, 2003). In the pre-antibioticera, the mortality of patients with S. aureus bacteremia exceeded80%, and over 70% developed metastatic infections (Skinner, 1941).The prognosis of patients with S. aureus infections improved dras-tically since the introduction of penicillin in the early 1940s.However, already a few years later, the rst S. aureus strains resis-tant against penicillin emerged in hospitals (Rammelkamp andMaxon, 1942). In the 1960s, a new semi-synthetic antibiotic methicillin was introduced for treatment of staphylococcal infec-tions. Also in this case, the rst methicillin resistant S. aureus strains(MRSA) were already observed within a period of two years afterthe introduction of this antibiotic (Lowy, 2003). The rst infec-tions caused by MRSA used to be associated with hospitalizedpatients. This phenomenon is generally referred to as hospital-acquired MRSA (HA-MRSA). However, in recent years, the spread

see front matter 2013 Published by Elsevier GmbH.rg/10.1016/j.ijmm.2013.11.012

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53ed with Staphylococcus aureus

na M. van der Kooi-Pola, Jos C. Duipmansb, Marceten van Dijl a,

f Medical Microbiology, University of Groningen, University Medical Center Groningensf Dermatology, University of Groningen, University Medical Center Groningen, Hanzep

e i n f o

e xxx

a b s t r a c t

Patients with the genetic blistering dcan become colonized by different bac m/locate / i jmm

losa patients

Jonkmanb,

eplein 1, P.O. Box 30001, 9700 RB Groningen,

P.O. Box 30001, 9700 RB Groningen, The

epidermolysis bullosa (EB) often have chronic wounds that, especially the opportunistic pathogen Staphylococcus aureus.


ARTICLE IN PRESSG ModelIJMM 50775 192 M.M. van der Kooi-Pol et al. / International Journal of Medical Microbiology xxx (2013) xxx xxx

Fig. 1. Chronistaphylococcarecessive dystsimplex (EBS-

of so-calledan addition1982; Meraeages easilythey have ntions with estrains (Pattion on theimmune-corier functiothe S. aureudisease epichronic wofew other maeruginosa of the studidened as tover periodBy contrastfew wound

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73 this article in press as: van der Kooi-Pol, M.M., et al., Hostpathogen interccus aureus. Int. J. Med. Microbiol. (2013), http://dx.doi.org/10.1016/j.ijmm.2

c wounds of patients with epidermolysis bullosa. The images show typical examples ol wound colonization. Specically, these patients were diagnosed with: (A) Herlitz-typrophic epidermolysis bullosa (RDEB); (C and D) non-Herlitz-type junctional epidermolysDM).

community-acquired MRSA (CA-MRSA) strains has laidal burden on the healthcare system (Saravolatz et al.,

et al., 2011). In contrast to HA-MRSA, the CA-MRSA lin- spread within the young and healthy community, andow entered into hospitals causing nosocomial infec-ven higher mortality rates than the hospital-acquiredel et al., 2007; Moore et al., 2009). This focuses atten-

risks of severe staphylococcal infections for frail andmpromised patients, or patients whose primary bar-n of the skin is impaired. The present review addressess colonization of patients with the genetic blisteringdermolysis bullosa (EB), who often suffer from largeunds that are readily colonized by staphylococci and aicrobes, such as Streptococcus species, and Pseudomonas(Brandling-Bennett and Morel, 2010). For the purposees reviewed here, EB patients with chronic wounds arehose patients who have multiple non-healing woundss of more than 3 months (van der Kooi-Pol et al., 2012)., EB patients without chronic wounds have relativelys that heal in shorter periods of time.

Epidermol

S. aureuers of the immune reis differentConsequeninfection bywith cysticCallaghan aMena et aldefective bied to lesseto a group EB develop(Marinkoviskin is dueand at the ebe distingutering. EB sactions in epidermolysis bullosa patients colonized with013.11.012

f chronic wounds of patients with EB as included in our studies one junctional epidermolysis bullosa (JEB-H); (B) severe generalized

is bullosa (JEB-nH), or (E) Dowling-Meara type epidermolysis bullosa

ysis bullosa

s infections are usually limited by the primary barri-skin and mucosa, as well as the innate and adaptivesponses of healthy individuals. However, the situation

in patients where these defenses are compromised.tly, such patients may suffer from colonization and

S. aureus. This has been extensively studied in patients brosis or atopic dermatitis (Johannessen et al., 2012;nd McClean, 2012; Goss and Muhlebach, 2011; Balma-., 2011; Kahl, 2010). In other groups of patients witharriers, the interactions with S. aureus have been stud-r extents. One of these diseases is EB, which refersof inherited mechano-bullous disorders. Patients with

blisters as a consequence of trivial mechanical traumach, 1999; Fine and Hintner, 2009). The fragility of their

to defects in structural proteins within the epidermispidermaldermal junction. Four major EB subtypes canished based on the ultrastructural characteristics of blis-implex (EBS) is characterized by cleavage of basal cells

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

Please cite interactions in epidermolysis bullosa patients colonized withStaphyloco mm.2013.11.012

ARTICLE IN PRESSG ModelIJMM 50775 19M.M. van der Kooi-Pol et al. / International Journal of Medical Microbiology xxx (2013) xxx xxx 3

within the epidermis. In junctional EB (JEB), subepidermal cleavageoccurs between the lamina densa and the basal cells. The Herlitztype JEB (JEB-H) which is rarer and more severe than non-Herlitztype JEB (JEB-nH), is caused by null mutations in the genes forlaminin-33dermal basof laminin-ing with peet al., 2010the laminaized by mixAccordinglysies for eleantigenic mHepenstal, precise muwhich is imZambruno, gest that thfor EB (Sarkincidence alion live bir2010). In thmillion liveinhabitants25% with (Jonkman ecan vary wiof the skin ((Schober-Flit is conceivremained u

Bacterial w

The ulceopment of waureus in pa2010). In gebacterial prcritical colo(Fig. 2). Impbeing contaganisms ar(Dow et al., such contamwound healing microordamage (Dosition stateThis is reprin the wountypical signet al., 2003depends onamount of of the resperesponses oacterized ba wound wsymptoms opain, odor Tredget, 20treated haveven sepsis

chematic representation of the bacterial presence in wounds. The bacteriale in wounds can be categorized by four different conditions: contamination,tion, critical colonization and infection. Ultimately, this can lead to invasive, such as sepsis.

dapted from Edwards and Harding (2004).

zatio

deterposesgate

of 6012,ectedo inal., 2ined

hronred fans

pat Furtts wient

requency of S. aureus detected in patients with EB. A distinction was made EB patients without chronic wounds (white bars) and EB patients withwounds (black bars). The statistical signicance of observed differences was

using two-tailed independent student t-tests. Differences with P-values ofe marked with one star (*), and differences with P-values of 0.001 arewith two stars (**).

s were derived from van der Kooi-Pol et al. (2012, 2013a).

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155 this article in press as: van der Kooi-Pol, M.M., et al., Hostpathogen ccus aureus. Int. J. Med. Microbiol. (2013), http://dx.doi.org/10.1016/j.ij

2, an important trimeric adhesion protein in the epi-ement membrane (Yuen et al., 2012). In the absence332, the skin is prone to generalized painful blister-rsistent erosions and granulation tissue formation (Kho). In dystrophic EB (DEB) the cleavage occurs below

densa. The so-called Kindler syndrome is character-ed cleavage planes through the skin (Fine et al., 2008a)., a precise diagnosis of the type of EB is based on biop-ctron microscopic analysis and immunouorescenceapping (Pohla-Gubo et al., 2010; Eady and Dopping-2010). Furthermore, through sequence analysis thetation responsible for the disease can be determined,portant for conrmation of the diagnosis (Castiglia and2010). The overall world-wide EB prevalence data sug-ere is no gender, racial, or geographical predispositionar et al., 2011). In the United States of America (USA), thend prevalence of EB have been estimated at 19 per mil-ths and 8 per million inhabitants, respectively (Fine,e Netherlands, the incidence of EB is 100 new cases per

births, and the prevalence is 45 patients per million. Of these patients, 40% have been diagnosed with EBS,JEB, 35% with DEB and 0.4% with Kindler syndromet al., 2003). Depending on the type of EB, the symptomsdely in severity, ranging from minor to severe blisteringFig. 1), and even to a lethal form involving other organsores, 1999). In view of this large variation in symptoms,able that the clinically milder forms of EB have so farnderestimated (Sarkar et al., 2011).

ound colonization

ration of the skin in patients with EB leads to the devel-ounds that become colonized by different bacteria, S.

rticular (Brandling-Bennett and Morel, 2010; Mellerio,neral, four different stages can be distinguished in theesence in wounds, namely contamination, colonization,nization and infection (Edwards and Harding, 2004)ortantly, all chronic wounds should be considered asminated. In this case, mostly non-replicating microor-e present within a wound or on the wound surface1999). The host defenses are usually capable of clearinginants and, consequently, they do not interfere with

ing. Colonization is dened by the presence of replicat-ganisms adhering to a wound in the absence of tissuew et al., 1999). Critical colonization refers to the tran-

between colonization and invasive wound infection.esented by conditions where the bacterial bio-burdend reaches levels that interfere with healing, while thes and symptoms of infection are not produced (Schultz). Whether the colonizing organism invades the tissue

a number of microbe-host interactions, such as thebacteria per gram tissue, virulence and pathogenicityctive bacteria and proper innate and adaptive immunef the host (Wysocki, 2002). Wound infection is char-y the presence of replicating micro-organisms withinith subsequent host injury (Dow et al., 1999). Typicalf wound infection include erythema, warmth, swelling,and purulent drainage (Lipsky et al., 2012; Raa and11). Notably, wound infections that are not adequatelye a potential to progress into systemic infections and

(Raa and Tredget, 2011).

Fig. 2. Spresenccolonizadiseases

Figure a

Coloni

To predisinvesticohortet al., 2unexpbut alsPol et determwith cmeasuKluytmpled EB2012).patienafore-m

Fig. 3. Fbetweenchronic assessed0.05 armarked

Numbern of patients with EB

mine how the absence of the protective skin barrier EB patients for colonization by S. aureus, we recently

d the nasal, throat and wound colonization rates in a2 EB patients from the Netherlands (van der Kooi-Pol

2013a). Over a period of about 2 years, this revealed anly high rate of colonization not only in their wounds,

the anterior nares and throat (Fig. 3; van der Kooi-012, 2013a). Specically, the nasal colonization rates

for EB patients (62% or 75% for patients without oric wounds; Fig. 3) were substantially higher than thoseor healthy individuals (2537%) (Wertheim et al., 2005;et al., 1997), or healthcare workers who met the sam-ients at regular intervals (39%) (van der Kooi-Pol et al.,hermore, while the S. aureus throat colonization in EBthout chronic wounds (26%) was similar to that of theioned healthcare workers (23%), it was substantially

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

Please cite interStaphyloco mm.2


higher in EB patients with chronic wounds (55%) (van der Kooi-Pol et al., 2012). Importantly, the wounds of patients with EB werefound to be highly colonized by S. aureus as, over time, this bac-terium was encountered in the wounds of 92% of the EB patientswith chronwithout ch2010; van ddemonstratof S. aureusof chronic Mellerio, 20tion, it mayThis view ising cause ofsepticemia of the patiepatients withis contextdie during with JEB-H numbers ofabsent frommay also exless suscepcolonization

InterestiMultiple-Lo(Schouls et that the collineages of thermore, respiratoryfrequently (imply that tprocess, a vses, which belong to tdence of thGrundmannEB patientsture in thechronic wotypes at onet al., 2012,from EB pathe patientout chronicIn 8.7% of ttype was enall sampledyear samplithe includeent S. aureuthese patieunderscorewere investquent typinIn this caseLocus Varia(Sabat et alspa-typing.colonies in twere locateoverlappedaureus isolato distinct m

S. aureus types are not mutually exclusive. Accordingly, we haveproposed that the general assumption that one individual is pre-dominantly colonized by one type of S. aureus does not apply toEB patients with chronic wounds. Here we envisage the follow-

narioatio

requenvirdividst anual p

occuifcu

thatientse thatiost. Ifts, bunizent tyn chrlococ

loco

viru-exp

2011nce volveoteinte ths, anlococn), img fache minan

(Sibarrye varn facdsaybserpletredime a

to iny, 20

latte pro

lessto beus issurfaexpr2010may

the is rek, 20s areGill esult

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241


ic wounds, and in the wounds of 69% of the patientsronic wounds (Fig. 3) (Brandling-Bennett and Morel,er Kooi-Pol et al., 2012). Although this has not yet beened unambiguously, it seems likely that the high rate

wound colonization contributes to the developmentwounds in patients with EB (Kluytmans et al., 1997;10; Madsen et al., 1996; Grimble et al., 2001). In addi-

predispose EB patients to life-threatening infections. underscored by the observation that sepsis is a lead-

death amongst infants with EB in the USA. Specically,was associated with a cumulative risk of death for 17.5%nts with JEB-H by the age of 8 years, and for 24.2% of theth JEB-nH by the age of 15 years (Fine et al., 2008b). In

it should be noted that patients with JEB-H most oftenchildhood. Possibly, the high susceptibility of patientsto staphylococcal wound infections relates to the high

recurrent skin erosions. These are less prominent or the wounds of patients with other types of EB. Thisplain why patients with other types of EB seem to betible for invasive infections by S. aureus, despite high

rates (Yuen et al., 2011).ngly, the molecular typing of S. aureus isolates bycus Variable number tandem repeat Analysis (MLVA)al., 2009) and spa-typing (Harmsen et al., 2003) revealedonization of EB patients is not limited to specic geneticS. aureus (Fig. 4) (van der Kooi-Pol et al., 2012). Fur-autoinoculation of staphylococci between the upper

tract and wounds of EB patients was shown to occurvan der Kooi-Pol et al., 2012). Together, these ndingshe colonization of EB patients by S. aureus is a randomiew that is clearly supported by our spa-typing analy-showed that most of the identied S. aureus spa-typeshe most predominant spa-types in the areas of resi-e respective EB patients (van der Kooi-Pol et al., 2012;

et al., 2010). Thus, the S. aureus population structure in appears to mirror the local S. aureus population struc-

Netherlands. It was also found that EB patients withunds were colonized by up to six different S. aureuse particular time point of sampling (van der Kooi-Pol

2013a,b). Notably, the comparison of S. aureus isolatestients over a period of 2 years showed that 58.3% ofs with chronic wounds and 43.5% of the patients with-

wounds carried alternating S. aureus types over time.he patients without chronic wounds, a different MLVAcountered in each sampling round. Merely 42.5% of

patients carried the same S. aureus type over the 2-ng period. Altogether, these observations showed thatd EB patients were continuously challenged by differ-s types, and that the S. aureus population carried by

nts was subject to rapid changes. This conclusion wasd by studies in which the chronic wounds of EB patientsigated by replica-plating of used bandages and subse-g of S. aureus isolates (van der Kooi-Pol et al., 2013b)., an initial typing screen was performed by Multiple-ble number of tandem repeats Fingerprinting (MLVF)., 2012, 2013), which was then rened by MLVA and

This revealed that distinct S. aureus types formed micro-he wounds of EB patients. Notably, these microcoloniesd in close proximity to each other, and sometimes even

(van der Kooi-Pol et al., 2013b). While some adjacent S.tes belonged to closely related types, others belongedolecular complexes. This implies that these different

ing scecolonizmost fdiate ethis inthe hoindividrapidlymore dnichesEB patincreascolonizthe hopatienbe colodifferetions istaphy

Staphy

Thesurfaceet al., adheretors inand prpromokinasestaphyductioclottinaging tdetermagentstions cand thevasioand Linwere obe comaffect pThe sadictedLindsain thesurfacemay beneeds S. aurein cell ferent et al., genes One ofwhich(Novicsystemlence (may reactions in epidermolysis bullosa patients colonized with013.11.012

for staphylococcal colonization. Presumably, the initialn of an individual is a random process in which thently occurring S. aureus types in the individuals imme-

onment have the highest chance to be transmitted toual. Subsequently, the colonizing strain(s) will adapt tod vice versa. Compared to patients with EB, a healthyrovides only a limited niche for staphylococci, which ispied by the best-adapted strain. Subsequently, it will belt for other S. aureus types to conquer the possible host

are already occupied. This situation is very different in where especially large chronic wounds substantiallye chances of successful transmission, the subsequentn by multiple S. aureus types, and their adaptation to

so, this has important implications, not only for EBt also for other patients with chronic wounds that mayd by multiple S. aureus types. Clearly, the presence ofpes of this opportunistic pathogen at high concentra-onic wounds could represent a serious risk for severecal infections.

ccal virulence factors

lence of S. aureus is caused by a broad range of cellosed or secreted factors (Sibbald et al., 2006; Dreisbach). These include surface-exposed proteins involved inand colonization of host tissues, surface-exposed fac-d in the inhibition of phagocytic engulfment (capsule

A), invasins exported into the host environment toe bacterial spread in invaded tissues (e.g. leukocidin,d hyaluronidase), biochemical properties that enhancecal survival in phagocytes (carotenoid and catalase pro-munological disguises (protein A, Sbi, coagulase, and

tor), superantigens (egc and non-egc SAgs), toxins dam-embrane of host cells (hemolysins and leukotoxin), andts for inherent and acquired resistance to antimicrobialbald et al., 2006). It is known that S. aureus popula-

a range of unique variants of these virulence factors,iation in genes coding for surface proteins and immunetors has been shown to be lineage-specic (McCarthy, 2010; Ziebandt et al., 2010). In particular, variationsved for genes encoding surface proteins. These mayely absent, or they may be truncated which can thencted functional domains (McCarthy and Lindsay, 2010).pplies also to genes encoding secreted proteins pre-teract with the host immune system (McCarthy and10). It has been suggested that the level of variationr genes may be less drastic than in genes encodingteins, and that their complete absence or truncation

common (McCarthy and Lindsay, 2010). However, this veried by the detailed analysis of larger numbers ofolates of different types and origin. Notably, variationsce-exposed and secreted proteins can also relate to dif-ession levels in different S. aureus lineages (Ziebandt). The variations in the expression levels of virulence

relate to differential activities of specic regulators.key regulators of virulence factor genes is the RNAIII,sponsible for their cell density-dependent expression03). In addition, at least 16 two-component regulatory

to different extents involved in staphylococcal viru-t al., 2005). Strain-specic differences in gene regulationin very different cell surface proteome (surfacome) and

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301



Fig. 4. Generaaureus isolatesof each circle ior chronic wou

Reproduced fr

exoproteomin vitro (Dre

Notably,to relate toKrishna anet al., 2011the most imeap), immuremodelinggenes encoscribed (Bugenes encoand hla areseem to beS. aureus ingenes invo(Malachow

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317


l S. aureus population structure in the Netherlands. The minimal spanning tree was based from the nose and/or throat of EB patients are marked by green circles. S. aureus isolates indicative for the number of S. aureus isolates with the respective MLVA type. The treends (W) of an EB patient (no. 44) are indicated with arrows.

om van der Kooi-Pol et al. (2012).

e patterns as have been shown for S. aureus cells grownisbach et al., 2010, 2011; Ziebandt et al., 2010).

changes in the expression of virulence factors seem different host environments (Burian et al., 2010a,b;d Miller, 2012; Loughman et al., 2009; Malachowa). In nasally carried S. aureus cells, the genes encodingportant adhesion molecules (e.g. clfB, isdA, fnbA, atlA,

ne-modulating factors (sak, chp, spa) and cell surface factors (sceD, oatA, atlA) are highly expressed, whileding major toxins (hla, psm) are not detectably tran-rian et al., 2010a,b). In contrast, in cutaneous abscesses,ding toxin components, such as lukS-PV, lukE, hlgB

up-regulated, while RNAIII, bsaB and spa expression down-regulated (Loughman et al., 2009). In addition,cubated in human serum or blood up-regulates thelved in iron and iron transport-associated moleculesa et al., 2011). Taken together, it can be concluded

that S. aureenvironmenulence factoresponses mlence factocolonizing o

Antistaphy

The immlococcal prhuman indiit was repotoxic shocktoxin A (SEpersistent 2009). Antiactions in epidermolysis bullosa patients colonized with013.11.012

on MLVA of 23,000 S. aureus isolates of which 90% were MRSA. S.s from the wounds of EB patients are marked by red circles. The size

locations of S. aureus isolates from the upper respiratory tract (URT)

us shows major adaptive responses to different hostts by changing the expression of different groups of vir-rs. Consistent with this idea, specic adaptive immuneight be raised against different staphylococcal viru-

rs, depending on the site of infection as well as ther invading strain.

lococcal immune responses in EB patients

une responses against S. aureus and different staphy-oteins have been studied extensively both in healthyviduals as well as patients with different diseases. Thus,rted that the levels of antibodies directed against the

syndrome toxin 1 (TSST-1), staphylococcal entero-A) and ClfA and ClfB are signicantly higher in healthycarriers than in healthy non-carriers (Verkaik et al.,-staphylococcal antibody levels were shown to increase

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333



Fig. 5. IgG resage-matched hIgG levels agaiMLVA type (gr

Reproduced fr

strongly du(Kolata et aapplied in cold shock (Lorenz et aing bacteremcarried by tG (IgG) bindonizing strahigher antiindividualsKooi-Pol et important vthe secreteantigens (Sand LytM pret al., 2010)SEO are am(Holtfreter patients anonly low levGrumann epatients are

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355


ponses of EB patients to staphylococcal antigens. (A) The IgG levels against 43 puriedealthy controls (blue triangles; n = 14) were determined by Luminex assays. Median unst 43 S. aureus antigens in sera of EB patients colonized by multiple S. aureus MLVA typeeen diamonds; n = 7) were determined by Luminex assays. MFI values are marked with r

om van der Kooi-Pol et al. (2013a).

ring the course of infection in patients with bacteremial., 2011; Verkaik et al., 2010; Lorenz et al., 2000). Thisparticular to antibodies against IsaA, IsaB, the majorprotein (CspA) and the phosphocarrier protein (Hpr)l., 2000). In addition, Kolata et al. have shown that dur-ia caused by exogenous S. aureus strains (i.e. strains not

he patient), there was an increase of immunoglobulinsing to antigens from the invasive strain, but not the col-in (Kolata et al., 2011). In patients with EB, signicantly-staphylococcal IgG levels have been observed than in

of an age-matched healthy control group (Fig. 5; van deral., 2013b). Specically, this applied to IgGs against nineirulence factors: the surface proteins IsdA and SasG,

d proteins IsaA, SCIN, Nuc and LytM, and the super-Ags) SEM, SEN and SEO. Notably, the IsaA, SCIN, Nuc,oteins are expressed by many S. aureus types (Ziebandt. Also, the egc gene cluster-encoded SAgs SEM, SEN andongst the most prevalent SAgs of S. aureus (5266%)et al., 2007). Intriguingly, persistent carriers, bacteremiad furunculosis patients were found to develop no, orels of antibodies against these SAgs (Burian et al., 2012;t al., 2011; Holtfreter et al., 2011). This suggests that EB

more signicantly challenged by egc SAgs than healthy

carriers andof multipleIgG levels, apatients colcolonized best antistapmultiple S.IgGs againtionally, a slevels in sersamples frogether, thesresponses odue to the hIn the rst ptrations of their life. Seby S. aureusinvasive epWhile therelular adaptthe observehumoral adactions in epidermolysis bullosa patients colonized with013.11.012

S. aureus antigens in sera of EB patients (red diamonds; n = 13) ororescence intensity (MFI) values are marked by color-coded bars. (B)s (red triangles; n = 5), or EB patients colonized by only one S. aureused and green bars.

bacteremia or furunculosis patients. Also the carriage S. aureus strains has an impact on anti-staphylococcals shown by the comparison of the IgG responses of EBonized by only one S. aureus MLVA type with EB patientsy multiple S. aureus MLVA types. Interestingly, the high-hylococcal IgG levels were observed in patients carrying

aureus MLVA types. This was particularly evident forst IsdA, LukD, HlgB, LytM, LukS, LukF and ETA. Addi-ignicant correlation between anti-staphylococcal IgGum, wound uid and sterile blister uid was detected inm one EB patient (van der Kooi-Pol et al., 2013a). Alto-e observations suggest that the high adaptive immunef EB patients against S. aureus are directly or indirectlyigh colonization rates with very diverse S. aureus types.lace, these patients seem to be exposed to high concen-

different staphylococcal antigens for the largest part ofcondly, as a consequence of the high-level colonization, it seems likely that these patients experience multipleisodes that can elicit strong adaptive immune responses.

are currently no data available concerning possible cel-ive immune responses of EB patients against S. aureus,d high anti-staphylococcal antibody levels suggest thataptive immune responses could be important to combat

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379



invasive staphylococcal infections. Lastly, innate immune mech-anisms may also be important for protecting EB patients againstsevere staphylococcal infections, but this has not been investigatedso far.

Staphyloco

The heations by patdue to trauenvironmenthe physication. Staphywith delaye1996). Intrhealing meabout the the molecuNotably, neing have be2013; Atharevealed ththe bacterithat are higmolecular dand animalaureus andRecent studre-epitheliabiolms potor 1 (Pastaand P. aeruinduced exthat have bever, it shouout with onwe know thmous. Specand evolvinEB (van der

At the mimplicated adherence p2009). In a wound closactivities (Acan interactcellular adhextracellulaand migratcells. In thethe wound prevented. S. aureus wastrain was uS. aureus-inHowever, thaureus facto

Conclusion

Altogeththe essentiaing the colothe host re

importantly in the context of the present review, it is currentlynot known to what extent S. aureus contributes to the initiationof chronic wound development in patients with EB, or to whatextent S. aureus colonization interferes with chronic wound healing

e pan of ia plac wo

with inof baentiaB. Thnds.potenre anies a

caren by

wled

authEpidepartmt. M.ojects T4-Butte

nces

J., Urdhylocotimoreopouler, H.ureushanismena,

et al., hyloco. Dermg-Ben

epideM., Gressionnt to . Micro

., Raporal stabli142

M., Wus durn, M.,. Micr, D., Zol. ClinT.W., t vert207.

Browiagnos2.h, A., us aurh, A., g the s., Dop

nosis , R., H196., 2010

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443


ccal interference with wound healing

lthy human skin is a fantastic barrier against infec-hogenic microorganisms. When this barrier is breachedma or disease, bacteria from the skin surface andt are able to gain access to underlying tissues wherel characteristics favor wound colonization and infec-lococcal wound colonization is frequently associatedd wound healing (Manson et al., 1992; Madsen et al.,iguingly, the interference of S. aureus with wound-chanisms is poorly understood and very little is knownrespective in-patient hostpathogen interactions atlar level (Madsen et al., 1996; Grimble et al., 2001).gative effects of bacterial colonization on wound heal-en clearly established in animal models (Pastar et al.,nasopoulos et al., 2006; Roche et al., 2012). This hase polymicrobial nature of non-healing wounds wherea are predominantly present in the form of biolmshly resistant to antimicrobial treatments. Any availableata are exclusively derived from in vitro experiments

models, where mainly the interactions between S. P. aeruginosa were investigated (Pastar et al., 2013).ies in a porcine cutaneous wound model showed thatlization was signicantly delayed by mixed-speciesssibly through suppression of keratinocyte growth fac-r et al., 2013). Furthermore, co-existence of S. aureusginosa in cutaneous wounds was shown to result inpression of particular staphylococcal virulence factorseen implicated in skin and wound colonization. How-ld be emphasized that these experiments were carriede S. aureus strain only (Pastar et al., 2013), whereasat the bacterial diversity in chronic wounds is enor-

ically, recent studies identied a plethora of differentg S. aureus types in the chronic wounds of patients with

Kooi-Pol et al., 2012, 2013a,b).olecular level, just one staphylococcal protein has beenin the delay of wound healing, namely the extracellularrotein (Eap) (Athanasopoulos et al., 2006; Joost et al.,

mouse wound-healing model, Eap was shown to delayure due to its anti-inammatory and antiangiogenicthanasopoulos et al., 2006). It has been shown that Eap

with adhesion molecules, such as the endothelial inter-esion molecule 1 as well as with adhesive proteins in ther matrix, thereby blocking integrin-mediated adhesiveory interactions of both inammatory and endothelial

presence of Eap, recruitment of inammatory cells tosite as well as neovascularization of the wound wereThe delay of the wound healing due to the presence ofs shown to be reversible when an isogenic Eap-decientsed, demonstrating that inhibition of wound healing infected wounds can be at least in part attributed to Eap.ese ndings do not exclude the possibility that other S.rs may also be involved in delayed wound healing.

s and future perspectives

er, it can be concluded that very little is known aboutl processes that take place within S. aureus cells dur-nization of human wounds, and the same is true forsponses to staphylococcal wound colonization. More

in thesnizatiobacterchroniicantlyresearcnisms the esswith Ein wouit will tion, castrategwoundnizatio

Ackno

TheDutch the DesupporCEU prprojecDutch

Refere

Aguilar, Stap(Bal

AthanasWebcus amec

Balma-MM., StapInt. J

Brandlinwith

Burian, ExprcieClin

Burian, MTeming e1414

Burian, aure

CallaghaOpin

Castigliamat

Corrah, quen201

Dow, G.,in d414

Dreisbaccocc

Dreisbaclin

Eady, R.Adiag

Edwards17, 9

Fine, J.D12.actions in epidermolysis bullosa patients colonized with013.11.012

tients. However, based on the extensive bacterial colo-the wounds of patients with EB, we hypothesize thaty major roles in the development and exacerbation ofunds, and that the colonizing bacteria interfere signif-h wound healing. Therefore, key objectives for future

this area should be to dene (i) the precise mecha-cterial wound colonization in patients with EB and (ii)l interactions between colonizing bacteria and patientsis will pinpoint the Achilles heel(s) of bacteria growing

Patients with EB may benet from such knowledge, astially lead to informed strategies for effective preven-d/or healing of chronic wounds. Such new therapeutic

re urgently needed, because the current approaches for do not effectively prevent or eliminate wound colo-

S. aureus and other bacteria.

gements

ors thank the anonymous patients with EB from thermolysis Bullosa Registry and healthcare workers froment of Dermatology at the UMCG for their continuous

M.v.d.K.-P. and J.M.v.D. were in parts supported by thet LSHG-CT-2006-037469 and the Top Institute Pharma213 and T4-502. J.C.D. and M.F.J. were supported by thery Child Foundation.

ay-Cornejo, V., Donabedian, S., Perri, M., Tibbetts, R., Zervos, M., 2010.ccus aureus meningitis: case series and literature review. Medicine) 89, 117125.os, A.N., Economopoulou, M., Orlova, V.V., Sobke, A., Schneider, D.,, et al., 2006. The extracellular adherence protein (Eap) of Staphylococ-

inhibits wound healing by interfering with host defense and repairs. Blood 107, 27202727.

A., Lara-Corrales, I., Zeller, J., Richardson, S., McGavin, M.J., Weinstein,2011. Colonization with community-acquired methicillin-resistantccus aureus in children with atopic dermatitis: a cross-sectional study.atol. 50, 682688.nett, H.A., Morel, K.D., 2010. Common wound colonizers in patientsrmolysis bullosa. Pediatr. Dermatol. 27, 2528.umann, D., Holtfreter, S., Wolz, C., Goerke, C., Broker, B.M., 2012.

of staphylococcal superantigens during nasal colonization is not suf-induce a systemic neutralizing antibody response in humans. Eur. J.biol. Infect. Dis. 31, 251256.

utenberg, M., Kohler, T., Fritz, M., Krismer, B., Unger, C., et al., 2010a.expression of adhesion factors and activity of global regulators dur-shment of Staphylococcus aureus nasal colonization. J. Infect. Dis. 201,1.olz, C., Goerke, C., 2010b. Regulatory adaptation of Staphylococcusing nasal colonization of humans. PLoS One 5, e10040.

McClean, S., 2012. Bacterial host interactions in cystic brosis. Curr.obiol. 15, 7177.ambruno, G., 2010. Molecular testing in epidermolysis bullosa. Der-. 28, 223229, viiviii.Enoch, D.A., Aliyu, S.H., Lever, A.M., 2011. Bacteraemia and subse-ebral osteomyelitis: a retrospective review of 125 patients. QJM 104,

ne, A., Sibbald, R.G., 1999. Infection in chronic wounds: controversiesis and treatment. Ostomy Wound. Manage. 45, 2327, 2940; quiz

van Dijl, J.M., Buist, G., 2011. The cell surface proteome of Staphylo-eus. Proteomics 11, 31543168.Hempel, K., Buist, G., Hecker, M., Becher, D., van Dijl, J.M., 2010. Pro-urfacome of Staphylococcus aureus. Proteomics 10, 30823096.ping-Hepenstal, P.J., 2010. Transmission electron microscopy for the

of epidermolysis bullosa. Dermatol. Clin. 28, 211222, vii.arding, K.G., 2004. Bacteria and wound healing. Curr. Opin. Infect. Dis... Inherited epidermolysis bullosa. Orphanet J. Rare Dis. 5, 12-1172-5-

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469470471472473474475476477478479480481482483484485486487488489490491492493494495496497498499500501502503504505506507508509510511



Fine, J.D., Eady, R.A., Bauer, E.A., Bauer, J.W., Bruckner-Tuderman, L., Heagerty, A.,et al., 2008a. The classication of inherited epidermolysis bullosa (EB): reportof the Third International Consensus Meeting on Diagnosis and Classication ofEB. J. Am. Acad. Dermatol. 58, 931950.

Fine, J.D., Johnson, L.B., Weiner, M., Suchindran, C., 2008b. Cause-specic risks ofchildhood

Fine, J.D., HintnMultidisci

Forsblom, E., nen, A., 20prospectivStaphyloco

Gill, S.R., FoutsInsights oanalysis obiolm-prteriol. 187

Goss, C.H., Mubrosis. J.

Grimble, S.A., aureus in p22, 21521

Grumann, D., R2011. Chabodies in S

Grundmann, HFriedrich, causing inPLoS Med.

Harmsen, D., 2003. Typipital settinmanagem

Holtfreter, S., Get al., 2007aureus isol

Holtfreter, S., et al., 2011ogous form30, 70771

Johannessen, Mthat may iInfect. Mic

Jonkman, M.F.bullosa duTijdschr. G

Joost, I., Blass,scription aaureus in a

Kahl, B.C., 201cystic bro

Kho, Y.C., RhoEpidemioldermolysibullosa. Ar

Kluytmans, J.,cus aureusMicrobiol.

Kolata, J., BodDistinctivebacteremi

Krishna, S., MStaphyloco

Lauderdale, Tet al., 2010depend onods, and t1553155

Lipsky, B.A., B2012. Infethe diagnoe132e173

Lorenz, U., Ohlbody respStaphyloco

Loughman, J.Asion in huDis. 199, 2

Lowy, F.D., 200Clin. Inves

Lowy, F.D., 199Madsen, S.M.,

healing ofMalachowa, N

Braughtonexpression

Manson, W.L., Pernot, P.C., Fidler, V., Sauer, E.W., Klasen, H.J., 1992. Colonizationof burns and the duration of hospital stay of severely burned patients. J. Hosp.Infect. 22, 5563.

Marinkovich, M.P., 1999. Update on inherited bullous dermatoses. Dermatol. Clin.17, 473485, vii.

y, A.J.immuhost, J.E., . 28, 2.M., S., 201hicillinear tr, L.A., tant pectiv.L., H. Comtant ShealthR.P., 20ccal v., Nuss of mginosa., Kum300 gus as aubo, Ghe dia, Tredgkampn of p.D., Reasingcted w.J., Budrview al sur.J., Ch, et aem-rehylocotz, Lhicillinmmun., Ban

an J. D-Flore. 11, 2

L.M.,en-Veat anahores

G.S., S. Wound Re

M.J., Z., 2006

secre D., 1y of oed wi518

Koochukohyloco-termatol.

Kooi-nsen,ronicKooi-uls, L.us stra466.

N.J., B. Heteus bac

N.J., d., 2009iers anm, H.F, et al.et Inf

512513514515516517518519520521522523524525526527528529530531532533534535536537538539540541542543544545546547548549550551552553554555556557558559560561562563564565566567568569570571572573574575576577578579580581582583584585586587588589590591592593594595596597


death in inherited epidermolysis bullosa. J. Pediatr. 152, 276280.er, H., 2009. Life with Epidermolysis Bullosa (EB): Etiology, Diagnosis,

plinary Care and Therapy. Springer, Wien, Austria.Ruotsalainen, E., Molkanen, T., Ollgren, J., Lyytikainen, O., Jarvi-11. Predisposing factors, disease progression and outcome in 430ely followed patients of healthcare- and community-associatedccus aureus bacteraemia. J. Hosp. Infect. 78, 102107., D.E., Archer, G.L., Mongodin, E.F., Deboy, R.T., Ravel, J., et al., 2005.

n evolution of virulence and resistance from the complete genomef an early methicillin-resistant Staphylococcus aureus strain and aoducing methicillin-resistant Staphylococcus epidermidis strain. J. Bac-, 24262438.hlebach, M.S., 2011. Review: Staphylococcus aureus and MRSA in cysticCyst. Fibros. 10, 298306.Magee, T.R., Galland, R.B., 2001. Methicillin resistant Staphylococcusatients undergoing major amputation. Eur. J. Vasc. Endovasc. Surg.8.uotsalainen, E., Kolata, J., Kuusela, P., Jarvinen, A., Kontinen, V.P., et al.,

racterization of infecting strains and superantigen-neutralizing anti-taphylococcus aureus bacteremia. Clin. Vaccine Immunol. 18, 487493.., Aanensen, D.M., van den Wijngaard, C.C., Spratt, B.G., Harmsen, D.,A.W., et al., 2010. Geographic distribution of Staphylococcus aureusvasive infections in Europe: a molecular-epidemiological analysis.

7, e1000215.Claus, H., Witte, W., Rothganger, J., Claus, H., Turnwald, D., et al.,ng of methicillin-resistant Staphylococcus aureus in a university hos-g by using novel software for spa repeat determination and databaseent. J. Clin. Microbiol. 41, 54425448.rumann, D., Schmudde, M., Nguyen, H.T., Eichler, P., Strommenger, B.,. Clonal distribution of superantigen genes in clinical Staphylococcusates. J. Clin. Microbiol. 45, 26692680.Jursa-Kulesza, J., Masiuk, H., Verkaik, N.J., de Vogel, C., Kolata, J.,. Antibody responses in furunculosis patients vaccinated with autol-alin-killed Staphylococcus aureus. Eur. J. Clin. Microbiol. Infect. Dis.7.., Sollid, J.E., Hanssen, A.M., 2012. Host- and microbe determinants

nuence the success of Staphylococcus aureus colonization. Front. Cell.robiol. 2, 56., Rulo, H.F., Duipmans, J.C., 2003. From gene to disease; epidermolysise to mutations in proteins in or around the hemidesmosome. Ned.eneeskd. 147, 11081113.

D., Burian, M., Goerke, C., Wolz, C., von Muller, L., et al., 2009. Tran-nalysis of the extracellular adherence protein from Staphylococcusuthentic human infection and in vitro. J. Infect. Dis. 199, 14711478.0. Impact of Staphylococcus aureus on the pathogenesis of chronicsis lung disease. Int. J. Med. Microbiol. 300, 514519.

des, L.M., Robertson, S.J., Su, J., Varigos, G., Robertson, I., et al., 2010.ogy of epidermolysis bullosa in the antipodes: the Australasian Epi-s Bullosa Registry with a focus on Herlitz junctional epidermolysisch. Dermatol. 146, 635640.

van Belkum, A., Verbrugh, H., 1997. Nasal carriage of Staphylococ-: epidemiology, underlying mechanisms, and associated risks. Clin.

Rev. 10, 505520.e, L.G., Holtfreter, S., Steil, L., Kusch, H., Holtfreter, B., et al., 2011.

patterns in the human antibody response to Staphylococcus aureusa in carriers and non-carriers. Proteomics 11, 39143927.iller, L.S., 2012. Hostpathogen interactions between the skin andccus aureus. Curr. Opin. Microbiol. 15, 2835..L., Wang, J.T., Lee, W.S., Huang, J.H., McDonald, L.C., Huang, I.W.,. Carriage rates of methicillin-resistant Staphylococcus aureus (MRSA)

anatomic location, the number of sites cultured, culture meth-he distribution of clonotypes. Eur. J. Clin. Microbiol. Infect. Dis. 29,9.erendt, A.R., Cornia, P.B., Pile, J.C., Peters, E.J., Armstrong, D.G., et al.,ctious Diseases Society of America clinical practice guideline forsis and treatment of diabetic foot infections. Clin. Infect. Dis. 54,.sen, K., Karch, H., Hecker, M., Thiede, A., Hacker, J., 2000. Human anti-onse during sepsis against targets expressed by methicillin resistantccus aureus. FEMS Immunol. Med. Microbiol. 29, 145153.., Fritz, S.A., Storch, G.A., Hunstad, D.A., 2009. Virulence gene expres-man community-acquired Staphylococcus aureus infection. J. Infect.94301.3. Antimicrobial resistance: the example of Staphylococcus aureus. J.t. 111, 12651273.8. Staphylococcus aureus infections. N. Engl. J. Med. 339, 520532.

Westh, H., Danielsen, L., Rosdahl, V.T., 1996. Bacterial colonization and venous leg ulcers. APMIS 104, 895899.., Whitney, A.R., Kobayashi, S.D., Sturdevant, D.E., Kennedy, A.D.,, K.R., et al., 2011. Global changes in Staphylococcus aureus gene

in human blood. PLoS One 6, e18617.

McCarthand and

MellerioClin

Mera, Ret almet10-y

Mermelresispros

Moore, C2009resisand

Novick, loco

Pastar, Itionaeru

Patel, MUSAaure

Pohla-Gfor t

Raa, K.Rammel

actioRoche, E

Incrinfe

Sabat, AOvelogic

Sabat, AN.E.tandStap

SaravolaMeta co

Sarkar, RIndi

SchoberNurs

Schouls,Santrepetrop

Schultz,2003Wou

Sibbald,et alative

Skinner,studcern68, 8

van derKyustaplongDerm

van derOmain ch

van der Schoaure463

Verkaik,2010aure

Verkaik,et alcarr

WertheiH.A.Lancactions in epidermolysis bullosa patients colonized with013.11.012

, Lindsay, J.A., 2010. Genetic variation in Staphylococcus aureus surfacene evasion genes is lineage associated: implications for vaccine designpathogen interactions. BMC Microbiol. 10, 173.2010. Infection and colonization in epidermolysis bullosa. Dermatol.67269, ix.uaya, J.A., Amrine-Madsen, H., Hogea, C.S., Miller, L.A., Lu, E.P.,1. Increasing role of Staphylococcus aureus and community-acquired-resistant Staphylococcus aureus infections in the United States: a

end of replacement and expansion. Microb. Drug Resist. 17, 321328.Cartony, J.M., Covington, P., Maxey, G., Morse, D., 2011. Methicillin-Staphylococcus aureus colonization at different body sites: ae, quantitative analysis. J. Clin. Microbiol. 49, 11191121.ingwe, A., Donabedian, S.M., Perri, M.B., Davis, S.L., Haque, N.Z., et al.,parative evaluation of epidemiology and outcomes of methicillin-taphylococcus aureus (MRSA) USA300 infections causing community-care-associated infections. Int. J. Antimicrob. Agents 34, 148155.03. Autoinduction and signal transduction in the regulation of staphy-

irulence. Mol. Microbiol. 48, 14291449.baum, A.G., Gil, J., Patel, S.B., Chen, J., Valdes, J., et al., 2013. Interac-ethicillin resistant Staphylococcus aureus USA300 and Pseudomonas

in polymicrobial wound infection. PLoS One 8, e56846.ar, R.A., Stamm, A.M., Hoesley, C.J., Moser, S.A., Waites, K.B., 2007.

enotype community-associated methicillin-resistant Staphylococcus cause of surgical site infections. J. Clin. Microbiol. 45, 34313433.., Cepeda-Valdes, R., Hintner, H., 2010. Immunouorescence mappinggnosis of epidermolysis bullosa. Dermatol. Clin. 28, 201210, vii.et, E.E., 2011. Infection control in the burn unit. Burns 37, 515., C.H., Maxon, T., 1942. Resistance of Staphylococcus aureus to theenicillin. Proc. Royal Soc. Exper. Biol. Med. 51, 386.enick, P.J., Tetens, S.P., Ramsay, S.J., Daniels, E.Q., Carson, D.L., 2012.

the presence of biolm and healing delay in a porcine model of MRSA-ounds. Wound Repair Regen. 20, 537543.imir, A., Nashev, D., Sa-Leao, R., van Dijl, J.M., Laurent, F., et al., 2013.of molecular typing methods for outbreak detection and epidemio-veillance. Euro Surveill. 18, 20380.lebowicz, M.A., Grundmann, H., Arends, J.P., Kampinga, G., Meessen,l., 2012. Microuidic-chip-based multiple-locus variable-numberpeat ngerprinting with new primer sets for methicillin-resistantccus aureus. J. Clin. Microbiol. 50, 22552262..D., Markowitz, N., Arking, L., Pohlod, D., Fisher, E., 1982.-resistant Staphylococcus aureus. Epidemiologic observations duringity-acquired outbreak. Ann. Intern. Med. 96, 1116.sal, S., Garg, V.K., 2011. Epidermolysis bullosa: where do we stand?ermatol. Venereol. Leprol. 77, 431438.s, C., 1999. Epidermolysis bullosa: a nursing perspective. Dermatol.43248, 253256.

Spalburg, E.C., van Luit, M., Huijsdens, X.W., Pluister, G.N., vanrheuvel, M.G., et al., 2009. Multiple-locus variable number tandemlysis of Staphylococcus aureus: comparison with pulsed-eld gel elec-is and spa-typing. PLoS One 4, e5082.ibbald, R.G., Falanga, V., Ayello, E.A., Dowsett, C., Harding, K., et al.,nd bed preparation: a systematic approach to wound management.pair Regen. 11 (Suppl. 1), S1S28.iebandt, A.K., Engelmann, S., Hecker, M., de Jong, A., Harmsen, H.J.,. Mapping the pathways to staphylococcal pathogenesis by compar-tomics. Microbiol. Mol. Biol. Rev. 70, 755788.941. Signicance of bacteremia caused by Staphylococcus aureus: ane hundred and twenty-two cases and a review of the literature con-th experimental infection in animals. Archives of Internal Medicine75.i-Pol, M.M., de Vogel, C.P., Westerhout-Pluister, G.N., Veenstra-va, Y.K., Duipmans, J.C., Glasner, C., et al., 2013a. High anti-ccal antibody titers in patients with epidermolysis bullosa relate to

colonization with alternating types of Staphylococcus aureus. J. Invest. 133, 847850.Pol, M.M., Sadabad, M.S., Duipmans, J.C., Sabat, A.J., Stobernack, T.,

T.F., et al., 2013b. Topography of distinct Staphylococcus aureus types wounds of patients with epidermolysis bullosa. PLoS One 8, e67272.Pol, M.M., Veenstra-Kyuchukova, Y.K., Duipmans, J.C., Pluister, G.N.,M., de Neeling, A.J., et al., 2012. High genetic diversity of Staphylococcusins colonizing patients with epidermolysis bullosa. Exp. Dermatol. 21,

oelens, H.A., de Vogel, C.P., Tavakol, M., Bode, L.G., Verbrugh, H.A., et al.,rogeneity of the humoral immune response following Staphylococcusteremia. Eur. J. Clin. Microbiol. Infect. Dis. 29, 509518.e Vogel, C.P., Boelens, H.A., Grumann, D., Hoogenboezem, T., Vink, C.,. Anti-staphylococcal humoral immune response in persistent nasald noncarriers of Staphylococcus aureus. J. Infect. Dis. 199, 625632.., Melles, D.C., Vos, M.C., van Leeuwen, W., van Belkum, A., Verbrugh,, 2005. The role of nasal carriage in Staphylococcus aureus infections.ect. Dis. 5, 751762.

603604605606607608609610611612613614615616617618619620621622623624625626627628629630631632633634635636637638639640641642643644645646647648649650651652653654655656657658659660661662663664665666667668669670671672673674675676677678679680681682683



Wysocki, A.B., 2002. Evaluating and managing open skin wounds: colonizationversus infection. AACN Clin. Issues 13, 382397.

Yuen, W.Y., Duipmans, J.C., Molenbuur, B., Herpertz, I., Mandema, J.M., Jonkman,M.F., 2012. Long-term follow-up of patients with Herlitz-type junctional epi-dermolysis bullosa. Br. J. Dermatol. 167, 374382.

Yuen, W.Y., Lemmink, H.H., van Dijk-Bos, K.K., Sinke, R.J., Jonkman, M.F., 2011. Herlitzjunctional epidermolysis bullosa: diagnostic features, mutational prole, inci-dence and population carrier frequency in the Netherlands. Br. J. Dermatol. 165,13141322.

Zervos, M.J., Freeman, K., Vo, L., Haque, N., Pokharna, H., Raut, M.,et al., 2012. Epidemiology and outcomes of complicated skin andsoft tissue infections in hospitalized patients. J. Clin. Microbiol. 50,238245.

Ziebandt, A.K., Kusch, H., Degner, M., Jaglitz, S., Sibbald, M.J., Arends, J.P., et al., 2010.Proteomics uncovers extreme heterogeneity in the Staphylococcus aureus exo-proteome due to genomic plasticity and variant gene regulation. Proteomics 10,16341644.

684685686687688689690691

692693694695696697698699 this article in press as: van der Kooi-Pol, M.M., et al., Hostpathogen ccus aureus. Int. J. Med. Microbiol. (2013), http://dx.doi.org/10.1016/j.ijactions in epidermolysis bullosa patients colonized with013.11.012

Hostpathogen interactions in epidermolysis bullosa patients colonized with Staphylococcus aureusStaphylococcus aureus harmless commensal or dangerous pathogen?Epidermolysis bullosaBacterial wound colonizationColonization of patients with EBStaphylococcal virulence factorsAntistaphylococcal immune responses in EB patientsStaphylococcal interference with wound healingConclusions and future perspectivesAcknowledgementsReferences

Documents

Bacaan POOl2104.pdf