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Quorum sensing
A mthod o cll
dnsity-dpndnt gn
rgulation in bactria. Quorum
snsing systms in
Gram-positiv bactria
commonly contain
pptid-basd scrtd signalsand a mmbran-locatd
snsor. Th staphylococcal
quorum snsing systm is
trmd agrand controls a
sris o gns involvd in
mtabolism and virulnc.
Antimicrobial peptide
A pptid such as a dnsin or
cathlicidin, which hav
antimicrobial activity.
Antimicrobial pptids ar
scrtd by th host, or
xampl, by pithlial clls or
into nutrophil phagosoms.
(Ref. 10) an th bifim-psiti cinica isat S. epi-dermidis rP62A9. Ntaby, n gnm squnc is ytaaiab f any isat f ST2, th mst fqunty
fun an ptntiay mst inasi ST.
An opportunistic pathogen
As pat f th human pithia micfa, S. epider-midis usuay has a bnign atinship ith its hst.Futhm, it has bn pps that S. epidermidismay ha a pbitic functin by pnting cnizatinf th hst by m s pathgns, such as S. aureus20.H, th is n ca inc inicating that S. epi-dermidis scts facts that ha an impact n thcnizatin f th micganisms in vivo.
Th is itt infmatin n th nn-infctius,cnizing ifsty fS. epidermidis. H, S. epi-dermidis infctins an th mchanisms by hichS. epidermidis pmts isas ha bcm incas-ingy stui. Amng th CNS, S. epidermidis caussth gatst numb f infctins2,5. In cinica mic-bigy, th CNS a ftn ft unchaactiz, asth main ga is t istinguish btn S. aureus anth staphyccci. H, fm th stuis in hichspcis intificatin has bn pfm1,5, it can bassum that mst nn-spcifi CNS infctins au t S. epidermidis. In paticua, S. epidermidis p-snts th mst fqunt causati agnt f infctins fining mica ics, such as pipha cntaintanus cathts (CvCs)5. Ths infctins usu-ay cmmnc ith th intuctin f bactia fm
th skin f th patint that f hath ca psnnuing ic instin an ha incas in numb,pbaby ing t th incas us f such ics1,21.Bstam infctins ccu in at ast 45 ut f y1,000 CvC instins pfm n patints in intnsica in th Unit Stats; at ast 22% f ths infctinsa caus byS. epidermidis1,21. In aitin t th abun-anc fS. epidermidis n th skin, this high fquncyf infctin is pbaby u t th abat mchanismsus t cniz catht sufacs (iscuss b).Futhm, S. epidermidis may b in in ps-thtic jint, ascua gaft, sugica sit, cnta nussystm shunt an caiac ic infctins5. Ntaby,
an scn ny t S. aureus,S. epidermidis causs ~13%f psthtic a ncaitis (Pve) infctins, ith ahigh at f intacaiac abscsss (38%) an 24% m-
taity22. H, Pve an th sius cmpicatinsa a amng S. epidermidis infctins, hich can bchaactiz as pminanty subacut an chnic.
Th fact that S. epidermidis s nt usuay causs infctins aiss th intsting qustin f hyit is aantagus f this spcis t maintain a f iunc. Massyet al. ha p a mathmati-ca m utining h f a spcis ith a high f asymptmatic tansmissin, such as S. epidermidis,aiunt stains ut-cmpt iunt stains, hasf spcis in hich asymptmatic tansmissin is ,such as S. aureus, iunt stains ut-cmpt aiu-nt stains23. This m is bas n th assumptinthat S. epidermidis is m aiy tansmissib thanS. aureus. Th auths xpain that this assumptin is
ai bcaus f th ispa cnizatin fS. epider-midis n human pithia (S. aureus amst xcusiycnizs th nas), th cnizatin f a humans ithS. epidermidis (S. aureus is ny fun in sm iniiu-as) an th spcific gntic facts in in cniza-tin an bactia intfnc, such as css-inhibitingquorum snsing signas (BOX 1). H, athugh qu-um snsing intfnc faus at ast n subtypfS. epidermidis S. aureusin vitro24,25, th is ninc that it has a in vivo20.
In accanc ith th iunc ptntia fS. epidermidis an th Massyet al. m, S. epider-
midis is quipp ith tminants that pmtpsistnc, such as immun asin mcus, aththan ths that aggssiy attack th hst, such astxins (iscuss b).
Evasion of host defences
Pathgns must a hst fncs t sui inth human by. Athugh ny a imit subst fhst fnc mchanisms, such as th puctinfantimicrobial pptids (AMPs), a psnt n humanskin26, S. epidermidis has t cp ith aius ai-tina mchanisms f hst fnc aft pntatin fth pithia bai. Th innat immun systm is th
Box 1 | Cross-inhibition of the agrquorum sensing system
Quorum sensing in staphylococci is accomplished by the agrsystem, which consists of an auto-inducing peptide (AIP)
precursor peptide maturation and export enzyme (AgrB) and a two-component signal transduction system (AgrC and
AgrA)146. Quorum sensing-controlled target genes ofagrare regulated directly by the DNA-binding protein AgrA or
through the regulatory RNAIII147,148. AIPs (or pheromones) are 7 to 9 amino acids in length and have a conserved cysteine
residue, the sulphhydryl group of which reacts with the carboxy-terminal carboxy group to form a thiolactone that is
essential for activity149,150. Binding of the AIP to AgrC stimulates AgrC to autophosphorylate, which in turn leads to
phosphorylation and activation of AgrA. AgrA activates the P2 promoter, which controls expression ofagrB, agrD, agrCandagrA, thereby closing the quorum sensing circuit. It also activates the P3 promoter, which drives expression of
RNAIII and the embedded phenol-soluble modulin-toxin (encoded by hld).In general, AIPs of self activate the agrresponse, whereas AIPs of non-self (different species or subgroups) inhibit the
agrresponse, unless the groups are closely related (for example, Staphyolococcus aureus agrtypes I and IV)146,151.
Staphylococcus epidermidis agrtype I is the type that is by far most frequently isolated from infections. The AIP of
S. epidermidis agrtype I inhibits all S. aureus agrtypes except for the rare type IV, whereas only S. aureus type IV
inhibits S. epidermidis type I152. Interference by quorum sensing cross-inhibition between S. aureus and S. epidermidis
therefore seems to be in favour ofS. epidermidis, but it is not known whether this has a role during colonization in vivo.
R E V I E W S
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Attachment to thepolymer surface
Attachment to hostmatrix proteins
Host matrix proteins:SdrF, SdrG, SdrH,Ebp, AtlE and Aae
Polymer surface:hydrophobicity, AtlE,Aae and teichoic acids
PNAG,teichoic acids,Bap andAap
PSMs?Proteases?
Cellcell adhesionand proliferation
Maturation
agrexpressionin exposed layers
Detachment
Innate host defence
A part o th immun systm
that provids th irst lin o
dnc, a ast rspons to
invading microorganisms, basd
on rcognition o pathogn-
associatd molcular pattrns.
Th innat immun systm
consists mainly o phagocyts,
platlts and scrtdantimicrobial pptids.
Neutrophil
Th most abundant lukocyt
in human blood. Nutrophils
ar th main clls that
liminat invading
microorganisms by uptak and
subsqunt killing through
ractiv oxygn spcis and
antimicrobial protins and
pptids.
Acquired host defence
A part o th immun systm
that dpnds on
antign-dpndnt clonal
xpansion o T and B clls atr
antign prsntation by
prossional antign-prsnting
clls. Th acquird rspons
provids long-trm humoral
(antibody-basd) and
cll-mdiatd immunity, but is
dlayd.
Sortase
An nzym that covalntly
links scrtd bactrial surac
protins to pptidoglycan.
Most o ths protins ar
substrats o sortas A and ar
charactrizd by an LPXTGamino acid moti at th
carboxyl trminus.
Teichoic acid
An anionic cll nvlop
glycopolymr producd by
Gram-positiv bactria,
composd o many idntical
sugarphosphat-rpating
units. Tichoic acids can b
linkd to pptidoglycan (wall
tichoic acids) or to th
cytoplasmic mmbran
through a lipid anchor
(lipotichoic acids).
fist in f fnc against an inaing micganismsuch as S. epidermidis an acts in a nn-spcific ay. Fxamp, as a ky pat finnat host dnc, nutrophilsingst bactia an ki thm using acti xygn sp-cis an AMPs27. S. epidermidis has sa mchanismst a bing ingst an ki by nutphis, asutin b.
Th f th spcific, acqui immun spns tS. epidermidis infctin is ss unst. Th factthat u immun systm has ifficutis caing ng-asting S. epidermidis infctins, spit th puctin fantibis against S. epidermidis ptins28, inicats thatth acquird host dnc systm might nt b fficintagainst S. epidermidis. This may b u, in pat, t S. epi-dermidis xpyms that ptct th cs fm anti-by cgnitin. Futhm, u immun systm mayha t act ss stngy t pant cnizingbactia.
Biofilm formation. Bifims a muticua, sufac-attach aggmatins f micganisms. Thyha a chaactistic physigy an achitctu thatfm th basis f bifim sistanc t many antibiticsan mchanisms f hst fnc6. In accanc ith
this gna ntin, S. epidermidis shs substantia,gnm-i aaptatin t th bifim m f gth,incuing nguatin f basic c pcsss suchas nucic aci, ptin an c a bisynthss29.Ths gn-guaty changs may xpain th imitactiity f many antibitics that tagt actiy gingcs (f xamp, pniciins30, amingycsis31 anquinns32) against S. epidermidis bifims.
Bifim fmatin pcs by th initia ahsin fcs t a sufac an thi subsqunt agggatin intmuticua stuctus (fIG. 1). Thf, th p-mnt f a bifim quis ahsi fcs f bth thcnizatin f sufacs an th cc intactins.
Disupti fcs a n f th fmatin f fui-fi channs that a imptant f nutint iyt a bifim cs an gi th matu bifim its typicath-imnsina stuctu. Disupti fcs a asin in th tachmnt f c custs fm th bi-fim, hich imits bifim xpansin an may a t thissminatin f infctin33.
Ahsin t abitic sufacs such as cathts ismainy gn by bactia c sufac hyph-bicity34. Spcific ptins that affct sufac ahsinin S. epidermidis, such as th abunant sufac ptinAte35, a bifunctina ahsin an autysin, an th Bapptin (as knn as Bhp)36, a iky t cntibut tth hyphbic chaact f th c sufac.
In vivo, matix ptins quicky c abitic su-facs such as ths f ining mica ics.S. epidermidis has a ast aay f sufac ptins caMSCrAMMs (micbia sufac cmpnnts cgniz-ing ahsi matix mcus) (TABLe 1), hich ha thptntia t intact ith matix ptins. MSCrAMMscan b canty bun t th bactia sufac bysortas A37 thugh as yt incmpty unst,nn-cant intactins ith sufac pyms suchas tichoic acids38(fIG. 2). Bining t fibingn an c-
agn has bn mnstat f th canty anchptins SG (as knn as Fb) an SF39,40, spc-tiy, has th nn-canty bun autysins Atean Aa sh a ss-spcific intactin an can bin tfibingn, fibnctin an itnctin35,41.
Th mst intnsiy stui MSCrAMM fS. epider-midis is SG, a fibingn-bining ptin that bngs tth sin/aspatat pat famiy. Th mmbs f thisfamiy, SF, SG an SH, a psnt in mst stainsfS. epidermidis42. SG has bn scib as ncs-say an sufficint t pmt S. epidermidis ahsint fibingn in vitro40,43 an pmts CvC-assciatinfctin in vivo44. SG bins t th thmbin caag
Figure 1 bfm vpmt Staphylococcus epidermidis. Attachment to uncoated material is mainly dependent
on cell surface hydrophobicity, whereas dedicated surface proteins mediate adhesion to host matrix-covered devices.
After adhesion to the surface, exopolysaccharide (for example, poly-N-acetylglucosamine (PNAG), also known as PIA),
specific proteins (Bap (also known as Bhp) and Aap) and accessory macromolecules (such as teichoic acids) aid
intercellular aggregation. Mechanisms of biofilm maturation, structuring and detachment are poorly understood but
possibly involve quorum sensing-controlled expression of detergent-like peptides and proteolytic activity in exposed
layers of the biofilm. The gene expression profile is markedly different in the biofilm compared with in the planktonic
mode of growth and includes downregulation of basic cell processes. PSM, phenol-soluble modulin.
R E V I E W S
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Table 1 | Virulence factors ofStaphylococcus epidermidis
Vu fat g Fut rf
Biofilm formation through primary attachment to abiotic surfaces
AtlE atlE An abundant bifunctional autolysin and
adhesin that affects surface hydrophobicity
35
Aae aae A bifunctional autolysin and adhesin 41
Teichoic acids Multiple biosynthetic genes In Staphylococcus aureus, teichoic acids
affect attachment (through the binding of
autolysins?)
49
Biofilm formation through primary attachment to matrix proteins
SdrF sdrF Binds to collagen 39,47
SdrG (also known as Fbe) sdrG (alsoknown as fbe) Binds to fibrinogen 43
SdrH sdrH Putative binding function only 42
Ebp ebp Binds to elastin (in S. aureus) 161
AtlE and Aae atlE andaae Bind to various matrix proteins 35,41
Intercellular aggregation
PNAG (also known as PIA) icaA, icaD, icaB and icaC An intercellular polysaccharide adhesin 52,56
Biofilm-associated protein Bap (also
known as Bhp)
bap (also known as bhp) An intercellular protein adhesin 36
Accumulation-associated protein Aap aap An intercellular protein adhesin precursor that
requires proteolytic processing for its activation
75,76
Teichoic acids Multiple biosynthetic genes Components of the biofilm matrix 50
Protective exopolymers
PNAG icaA, icaD, icaB and icaC Protects from IgG, AMPs, phagocytosis and
complement
97,98
PGA capA, capB, capC andcapD Protects from AMPs and phagocytosis 94
Resistance to AMPs
SepA protease sepA Involved in AMP degradation 122
Dlt, MprF, VraF and VraG dltA, dtlB, dtlC, dtlD, mprF, vraFandvraG Analogous to S. aureus, these proteins functionin thed-alanylation of teichoic acids (Dlt),
lysylation of phospholipids (MprF) and putative
AMP export (VraF and VraG)
111113
Aps system apsR (also known as graR),apsS (also known
as graS) and apsX
This system senses AMPs and regulates AMP
resistance mechanisms
110
Toxins
PSMs psm, psm, psm, hld, psm1 andpsm2 Pro-inflammatory cytolysins 29,92,106
Exoenzymes
Cysteine protease (SspB and Ecp);
S. aureus staphopain homologue
sspB Unknown: tissue damage? 87
Metalloprotease or elastase (SepA);
S. aureus aureolysin homologue
sepA Involved in lipase maturation, AMP resistance
and, potentially, tissue damage
86,122,153
Glutamylendopeptidase and serine
protease (GluSE, SspA and Esp);
S. aureus V8 protease homologue
sspA Degradation of fibrinogen and complement
factor C5
87,88
Lipases GehC and GehD gehC andgehD Persistence in fatty acid secretions? 154156
Other factors
Staphyloferrins sfna locus (S. aureus staphyloferrin A) Siderophores (iron acquisition) 157,158
SitA, SitB and SitC sitA, sitB andsitC An iron importer 159
FAME Unidentified Detoxification of bactericidal fatty acids 160
AMP, antimicrobial protein; FAME, fatty acid modifying enzyme; IgG, immunoglobulin G; PGA, poly--glutamic acid; PNAG, poly-N-acetylglucosamine;PSM, phenol-soluble modulin.
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Peptidoglycan
Aap
G5domains
A repeats/domain
Proteolyticprocessing
LPXTG
Lipoprotein
LPXTG
SD
LTA
WTA
AtIE
PGA
SdrG
PNAG
Brepeat
Ca2+Ca2+
Zn2+
Cytoplasmic membrane
A
sit in th B-chain f fibingn using a ck, ck anatch mchanism45. This mchanism is thught t a ta stabiiz MSCrAMMigan intactin. expssinf SG incass in an in vivo ninmnt46 an anti-bis t SG a psnt in human b42, mphasiz-ing th imptanc f SG f S. epidermidis infctin.rcnty, an imptant has as bn mnstatf SF uing nticua assist ic iin-atinfctin47. Sa aitina S. epidermidis MSCrAMMsha bn pict an ha ungn piminaychaactizatin48, athugh thi in matix ptinbining an iunc is nt yt unst.
Aft initia ahsin, bifims p thugh
intcua agggatin that is miat by many if-fnt sufac macmcus. Ths incu xp-ysacchai an ctain ptins, hich sm t bpminanty icat t th fmatin f th xta-cua bifim matix. In aitin, tichic acis49,50 anxtacua DNA iginating fm ys cs51 can haaccssy functins in agggatin, hich a iky t bpnnt n thi pyaninic chaact (fIG. 1).
Many S. epidermidis stains puc a py-N-actygucsamin (PNAG) hmpym, asnam PIA, that suuns an cnncts S. epider-midis cs in a bifim52(fIG. 3). This pym, hichiffs fm th PNAG pyms fun in natu
(such as chitin) by its 16 inkag52, has cnty asbn tct in many th micganisms, incuingYersinia pestis an Escherichia coli 53,54. Puctin fPNAG is cucia f bifim fmatin in vitro55,56 anhas a substantia impact n S. epidermidis bifim-ass-ciat infctin in mst anima ms5761. Th bisyn-thsis f PNAG is accmpish by th gn pucts fth ica (intcua ahsin) cus56. IcaA an IcaDpuc a chain fm actiat N-actygucsamin(GcNAc) mnms, th ngatin f hich ispnnt n th IcaC ptin, pbaby ing tth pict xpt functin f IcaC62. Patia -actyatin f th GcNAc sius is accmpish
by th c sufac-cat nzym IcaB aft xpt63.D-actyatin intucs psiti chags int th th-is-nuta pym that a imptant f sufacbining f PNAG an its aius bigica functinsin bifim fmatin an immun asin, hich aiscuss b63. Puctin f PNAG is subjct t aang f guaty infuncs64, incuing many g-ba iunc guats6571 but xcuing th quumsnsing guat agr72. It is ss unst hichninmnta signas cnt PNAG xpssin, pa-ticuayin vivo, but th cmpxity f this guatinhighights th imptanc f PNAG f S. epidermidispathphysigy.
Figure 2 | TStaphylococcusepidermidis ufa. Proteins such as SdrG and Aap can be attached to the cell
surface through sortase-catalysed covalent anchoring. These proteins harbour a characteristic LPXTG motif at the
carboxyl terminus, the threonine residue of which is linked to peptidoglycan. Many autolysins, such as AtlE, are anchored
non-covalently, probably through interactions with teichoic acids. Furthermore, lipoproteins are attached to the surface
through a fatty acid anchor that penetrates the cytoplasmic membrane. AtlE is a bifunctional adhesin and autolysin that
contributes to biofilm formation through its surface hydrophobicity and by binding to host matrix proteins. SdrG is an
example of the Sdr protein family of MSCRAMMs (microbial surface components recognizing adhesive matrix molecules).
Its serine/aspartate (SD) repeat region spans the peptidoglycan layer and its A region binds fibrinogen. The B repeats
harbour a Ca2+ binding EF-hand domain. Aap proteins aggregate through Zn2+-dependent G5 domains and form fibrils
that are likely to connect cells in the biofilm matrix. G5 domains also bind N-acetylglucosamine and can therefore interact
with poly-N-acetylglucosamine (PNAG, also known as PIA). In a step that is crucial for the function of Aap in intercellular
aggregation, the amino terminal region of the protein, comprising A repeats and the globular/domain, is
proteolytically removed. PNAG is cationic and probably interacts with negatively charged surface polymers such as
lipoteichoic acids (LTAs), wall teichoic acids (WTAs) and poly--glutamic acid (PGA). Green shading represents negative
charge and blue shading represents positive charge.
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N
ActivatedGlcNAc
NCC
C
PeptidoglycanTeichoic acids
IcaB
IcaC
icaR
sigB, sarAand luxS
icaA icaD icaB icaC
IcaDIcaA
GlcNAc-transferase
Export
N
a
b
1
2
3 De-acetylation
Pseudopeptide
A pptid that is ormd by
pptid bonds through
carboxyl groups othr than th
-carboxyl group.
M cnty, it as cgniz that PNAG is ntssntia f bifim fmatin in a S. epidermidisstains: stains that ack th ica gns can fm bi-fims73 an ica-ngati S. epidermidis stains habn isat fm bifim-assciat infctins74. Insm stains, bifim fmatin may b aitinay xcusiy miat by spcific sufac ptins,
namy Bap36 an Aap75. Th Aap ptin quisptytic actiatin76 an zinc ins77 f its bifim-pmting ffct. Zn2+ is cucia f th muaassciatin f s-ca G5 tanm pats77, hichmay uni th fmatin f Aap-bas fibi-ikstuctus n th bactia sufac78(fIG. 2). Th sammains a knn t intact ith GcNAc ancan thf ptntiay bin t PNAG, fming aptinpysacchai bifim ntk79. Bcausin vitro bifim fmatin can b pnt by achating agnt in th stng bifim-fming stainS. epidermidis rP62A, it has bn suggst that bi-fim fmatin in this stain is sy pnnt n
Aap77. In suppt f this bsatin, mncna anti-bis against Aap pnt bifim fmatin in thisstain80. H, this hypthsis is incnsistnt ithth pts that suppt pnnc n PNAG81an i nt fin ptin-miat bifim fmatint b imptant in th sam stain82. Thf, thcntibutin f ptins t S. epidermidis bifim f-matin an t th mchanisms in i quiintnsi futh instigatin. In aitin, th fin-ing that bifims cat sy ith ptins a ntas bust as ths cat ith PNAG74 inicats thatbth ptins an xpysacchai paticipat infficint S. epidermidis bifim fmatin.
Biofilm detachment. In cntast t intcua agg-gatin, bifim stuctuing an tachmnt a pyunst in S. epidermidis. w kn that bifimtachmnt in S. epidermidis is cnt by th qu-um snsing systm agr, bcaus bifims that a ys-functina in th agrsystm a thick an ha anbius fct in tachmnt72,83. In S. aureus, a m
has bn pps that ins agrxpssin in thxps ays f a bifim an pmts th tach-mnt f c custs fm th bifim sufac, thbycnting bifim xpansin84. likis, S. epidermidisagractiity is imit t th bifim sufac83, inicatingthat th is a cmmn staphyccca mchanism fquum snsing-cnt bifim tachmnt. Ttachmnt mchanisms ha bn pps: nzymaticgaatin f bifim xpyms an isuptin fnn-cant intactins by tgnt-ik mcus(fIG. 1). enzymatic gaatin f ptinacus bifimfacts has bn suggst as a mchanism fbifim tachmnt in S. aureus85, but inc f sucha functin f ptass in S. epidermidis has nt bnbtain. H, S. epidermidis s puc a sisf xptass ith substat spcificity that mays t ga sufac ptins8688. As f gaa-tin f bifim xpysacchai, staphyccci ntsm t ha a icat nzym f PNAG hyy-sis, in cntast t sa th bactia that pucPNAG89,90. Atnatiy, tgnt-ik mcus canisupt nn-cant (such as ctstatic an hy-phbic) intactins that ccu, f xamp, btnth catinic PNAG an aninic sufac pyms btn hyphbic gins f th bactia sufac.Th sht amphipathic phn-sub muins (PSMs)(f xamp, th S. epidermidis-txin; fIG. 4)ha bn
pps t ha such a functin91. S. epidermidis PSMsan xptass a stictyagr-guat92,93, ningsuppt t th ia that thy may b in in bifimstuctuing.
Protective exopolymers.S. epidermidis pucs xp-yms, namy py--gutamic aci (PGA) an PNAG,that ptct th bactium fm imptant mchanismsf innat hst fnc. Th psudopptid pym PGA,hich is synthsiz by th gn pucts f th capcus, is cucia f S. epidermidis sistanc t nutphiphagcytsis an AMPs, spit its s f puc-tin94. excpt fBacillus anthracis95, S. epidermidis is th
Figure 3 | T xpaa p-N-atuam. a | The
exopolysaccharide poly-N-acetylglucosamine (PNAG; also known as PIA), a partially
de-acetylated 1-6-linked N-acetylglucosamine (GlcNAc) homopolymer involved inimmune evasion and biofilm aggregation, is synthesized by the membrane-located
GlcNAc transferase IcaA, which needs the accessory IcaD membrane protein for
activity (step 1). The growing PNAG chain is probably exported by the IcaC membrane
protein (step 2). After export, IcaB de-acetylase, located on the cell surface, removes
some of the N-acetyl groups, giving the polymer a cationic character that is essential for
surface attachment (step 3). |The Ica proteins are encoded by the icagene locus
containing the icaADBCoperon and the icaR gene, which encodes a regulatory protein.
Expression of the icaADBC operon is regulated either directly at the icaA promoter orthrough expression of IcaR, both of which are controlled by a series of global regulatory
proteins (SigB, SarA and LuxS). Furthermore, insertion and excision of the IS256element
can turn PNAG expression off and on. Green shading represents negative charge and blue
shading represents positive charge. C, carboxyl; N, amino.
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0$,9*7,,.,,.$,,',)$.
0$4',,67,*'/9.:,,'791.)7..
0$$',,67,*'/9.:,,'791.)..
06,967,,(99.7,9',9..)..
0*,,$*,,.9,.6/,(4)7*.
0*,,$*,,.),.*/,(.)7*.
0$'9,$.,9(,9.*/,'4)74.
0()9$./).)).'//*.)/*11
0),,1/9..9,6),.*/)*11(1(
0(*/)1$,.'797$$,11'*$./*76,96,9(1*9*//*./)*)
07*/$($,$1794$$44+'69./*76,9',9$1*9*//*./)*)
06./$($,$179.$$4'4':7./*76,9',9(6*969/*.,)*)
0(4/)'$,5699'$*,14':64/$6*,$*,9(1*,69,6.//*4
0./)1$).',/($$,71'*74/*$6,91,,(669'0915)/*1
S. aureusPSM4S. aureus-toxin
S. epidermidis-toxinS. epidermidisPSMS. aureusPSM1
S. aureusPSM2S. epidermidisPSMS. aureusPSM3
S. epidermidisPSMS. aureusPSM1
S. aureusPSM2S. epidermidisPSM1
S. epidermidisPSM2S. epidermidisPSM3
-type
-type
Amphipathic -helix
Pathogen-associated
molecular pattern
A surac structur on
pathogns that is rcognizd
by th innat immun systm
as non-sl and triggrs
activation o innat host
dnc, usually by binding to
Toll-lik rcptors.
ny knn ganism in hich PGA has a functin inpathgnsis. Futhm, PGA pmts th gth fS. epidermidis at high sat cncntatins an is inucun ths cnitins94. This is miniscnt f PGApuctin in many haphiic bactia, in hich PGA isthught t cntibut t smtanc96, an inicats a f PGA uing S. epidermidis cnizatin. Finay,xpssin f th cap gns sms t b incas u-ing th bifim m f gth29. Intstingy, PGA ispsnt in many CNS but is absnt fm S. aureus9.
In aitin t its as pat f th xtacua bifimmatix, PNAG has bn fun t ptct S. epidermidisfm nutphi kiing, cmpmnt psitin, immu-ngbuins an AMPs97,98, an as fm Caenorhabditiselegans immun fncs in a nmat infctinm99. Th catinic PNAG ptcts cs fm AMPs fcatinic an aninic chag, inicating that its mchanismf actin may nt b imit t ctstatic pusin fAMPs f th sam chag98. It may thf as k bysqusting ppsity chag AMPs in a simia ay tth pps mchanism f ptctin fm tbamycinbyPseudomonas aeruginosa aginat100.
Pathogen-associated molecular patterns.Pathogn-associatd molcular pattrns (PAMPs) a stuctus nth bactia sufac that th innat immun systm c-gnizs as nn-sf thugh icat pathgn cg-nitin cpts (Prrs), such as th T-ik cpts(Tlrs)52. PAMPs such as ipptins an iptichicacis a cmmn in Gam-psiti bactia. rcgnitinf PAMPs actiats hst fnc mchanisms that incuphagcytsis an cytkin as101. Futhm, tha pts suggsting that sa aitina mcusthat a spcific t S. epidermidis may stimuat th innathst fnc spns. F xamp, PNAG as ptt stimuat Tlr2(Ref. 102). rcgnitin f PNAG by th
human immun systm u b an intsting xam-p f th hi-an-sk intpay btn pathgnan hst, as this u man that a substanc us byS. epidermidis f immun asin can tigg innat hstfnc mchanisms. H, this has nt bn cn-fim using gntic tin mutants, hich u bimptant t u ut th pssibiity that cntaminatingp-infammaty substancs (f xamp, ipptins) th basis f th bs ffct; such cntamina-tin has t fqunt misintificatin f agTlr2 stimuats103105. Simiay, th p-infammatycapacitis fS. epidermidis PSMs106 ha nt yt bncnfim using synthtic pptis gn tinmutants. H, S. epidermidis PSMs a simia tS. aureus PSMs, f hich hst fnc tigging actiityhas bn cnfim107, hich inicats that th scibp-infammaty ffct fS. epidermidis PSMs is gnu-in, athugh th actiatin f Tlr2 by PSMs108 hasnt bn ifi. Finay, an unusua sht-chain p-infammaty iptichic aci has bn scib inS. epidermidis109. H, chmica chaactizatin fth puifi mcu i nt inicat that this mcuis a tichic aci-at pym, an thus th intity f
this mcu an its p-infammaty actiity mainsunknn. Thf, th is a ca n f futhchaactizatin fS. epidermidis mcus that actiathst fncs.
Sensing antimicrobial peptides. Just as th humanimmun systm cgnizs S. epidermidis PAMPs, S. epi-dermidis has mchanisms t sns th psnc f hamfumcus puc by th hst. An AMP-snsing sys-tm tm aps has bn intifi that is actiat by aang f AMPs an tiggs upguatin f staphycc-ca AMP-fnsi mchanisms110(fIG. 5). Ths mcha-nisms incu th d-aanyatin f tichic acis111 an
Figure 4 | P-u mu. A sequence alignment ofStaphylococcus epidermidis and Staphylococcus aureus
phenol-soluble modulins (PSMs) is shown. PSMs serve as immune evasion molecules to their bacterial producer and as
pathogen-associated molecular patterns (PAMPs) for pathogen recognition to the host. All PSMs contain an amphipathic
-helix and amino-terminal N-formyl methionine, as they are secreted without post-translational processing, in an
unknown manner. PSMs of the -type are short, containing approximately 2025 amino acids. The S. aureus PSM
peptides 1 4 are strongly cytolytic. PSMs of the -type are longer (~45 amino acids) and do not have any substantial
cytolytic activity. Only the-toxin, an-type PSM with moderate cytolytic activity, and the -type PSMs are secreted by
S. epidermidis in large amounts. Despite being part of the psmoperon, the PSM3 peptide is not found in S. epidermidisculture filtrates, for unknown reasons. The psm1 gene is duplicated in some strains ofS. epidermidis.
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+ ++ +
|
Repulsion
Repulsion
Anionic cell surface
MprF
ApsX
ApsR
ApsS
Teichoicacid
Cationic AMP
D-alanylation ofteichoic acids
Lysylation ofphosphatidylglycerol Export by VraFG
DItA
DItC
DItB
DItD
D-Ala
VraFG
Activation ofaps-controlledresistance mechanisms
D-Ala
D-Ala D-Ala
D-Ala
+
+
+
+
Two-component system
A bactrial snsory systmcomposd o a mmbran-
locatd snsor (histidin
kinas) and a cytoplasmic
DNA-binding rgulatory
protin (rspons rgulator).
Th autophosphorylation-
dpndnt activation o
two-componnt systms is
triggrd by an xtracllular
signal.
Enterotoxin
A protin toxin rlasd by
a microorganism into th
intstin o its host.
th ysyatin f phsphipis by th MpF nzym112,bth f hich cas th aninic chag f th bactiasufac, thby pnting fficint attactin f catinicAMPs. Aitinay, th vaF an vaG ptins113 pssi-by functin as an AMP xpt by ming AMPs fmth cytpasmic mmban. Thf, th apssystm thfist xamp f an AMP sns in Gam-psiti bactia has a simia functin t th PhPPhQ AMP snsfun in Gam-ngati bactia114, but is nt utin-aiy at. Imptanty, th actiatin an ptctispns f th aps systm is imit t catinic AMPs.Futhm, th apssystm psnts a uniqu xampf a th-cmpnnt sns guat that cntains anssntia cmpnnt f unknn functin, ApsX, in ai-tin t th cassica cmpnnts f a two-componnt systm,
th histiin kinas ApsS (as knn as GaS) an thspns guat ptin, Apsr (as knn as Gar).
Toxins
In S. aureus, an many th bactia, txins a th mstimptant cntibuts t aggssi iunc. In cntastt th ast txin pti fS. aureus, S. epidermidis txinpuctin is msty imit t PSMs. Athugh stain-spcific puctin fntrotoxins has bn scib115,116,S. epidermidis is nt gnay accpt as an nttxinpuc. By cntast, in an auatin f ~200 S. epi-dermidis stains, a fun t puc PSMs xcptths stains that natuayagr-ysfunctina72,92,117
(fIG. 4). PSMs a chaactisticay sht, amphipathic,-hica pptis an ha p-infammaty an sm-tims cytytic functins. Th S. epidermidis-txin (asca PSM), a 24-amin aci ppti that iffs fmits S. aureus hmgu in ny n amin aci psitin,has bn suggst t b in in nctizing nt-citis in nnats118. Sm S. epidermidis PSMs aat t S. aureus PSMs that ha a pnunc capacityt ys human nutphis107. H, th PSM puc-tin pattn in S. epidermidis shs stng puctin fny th maty cytytic -txin an nn-cytytic-typ PSMs29. Thf, th PSM puctin pattn inS. epidermidis, in aitin t th gna absnc f highyaggssi txins in this spcis, is in cntast ith th highcytytic ptntia fS. aureus. This unpins th Massy
et al.23 m, hich ppss an utinay aantagf th aggssinss fS. epidermidis.
Colonization and pathogenesis
Sa stuis ha attmpt t intify th tmi-nants that istinguish S. epidermidis stains hich cancaus infctin fm ths that i n th skin. Thsstuis ith fcus n putati iunc tminants us gnm-i appachs such as cmpaatignmic hybiizatin1719,119. T main putati t-minants fS. epidermidis inasinss intifi inths stuis: th ica gns, hich guat th puc-tin f PNAG, an th instin mnt IS256. IS256is
Figure 5 | T atma ppt a uat Ap. Cationic antimicrobial peptides (AMPs) attach to the
negatively charged bacterial surface and membrane by electrostatic interactions, a prerequisite for AMP antimicrobial
activity that is often based on pore formation in the bacterial cytoplasmic membrane. The Staphylococcus epidermidis ApsS
AMP sensor has one short extracellular loop with a high density of negatively charged amino acid residues that interact with
cationic AMPs. Transduction of this interaction signal through ApsS and the essential accessory ApsX, which has an unknown
function, triggers the expression of key AMP resistance mechanisms. The d-alanylation of teichoic acids, which is carried out
by the products of the dltoperon, and lysylation of phosphatidylglycerol, which is catalysed by the MprF enzyme, result in the
decreased negative charge of the cell surface and membrane, respectively, leading to decreased attraction or repulsion of
cationic AMPs. The VraF and VraG ABC transporter also promotes resistance to AMPs and probably functions as an AMP
exporter. Green shading represents negative charge and blue shading represents positive charge.
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Colonization
Mechanical resistance (biofilm)
Immune evasion and AMPs
Immune evasion and AMPs
Immune evasion and AMPs
Osmoprotection
Adhesion to tissue
Pathogenesis
Mechanical resistance (biofilm)
Immune evasion, AMPs,immunoglobulins,
complement and phagocytosis
Immune evasion, AMPsand phagocytosis
Immune evasion and AMPs
Adhesion to tissue
PNAG
Biofilmproteins
(Aap and Bhp)
Protease(SepA)
PGA
MSCRAMMs
Methicillin
A pnicillin drivativ that is
rsistant to pnicillinas (an
nzym widsprad in
staphylococci that provids
rsistanc to pnicillin).
Mobile genetic element
DNA such as a plasmid or
transposon that can b
xchangd btwn bactria
by horizontal gn transr.
Mobil gntic lmnts otn
carry virulnc or antibiotic
rsistanc gns.
thught t cntibut t th gntic aaptatin that mayha a uing infctin65. F xamp, it may st abish th puctin f PNAG th functin f thagrgba iunc guat by insting int th ica agrci, spctiy83,120. Th catin f th ps-nc f PNAG ith th inasinss f th bactia mayb u t th s f this xpym in bifim fmatinan immun asin. In aitin, suts fm a humancnizatin m inicat that ica-ngati stains cann ha a scti aantag th ica-psiti stainsn th skin121. H, th inc suggsts that hncct f cna atnss, th a n iffncsbtn cmmnsa an infctius stains119.
Sa ins f inc inicat that mst iuncfacts fS. epidermidis iginay ha s in th cm-mnsa ifsty f this spcis (fIG. 6). Th pats payby PNAG, PGA an th SpA ptas in ptctingth bactium fm AMPs inicat that ths pymsas ha a ky uing if n th skin63,94,122, h
AMPs a a maj tminant f innat hst fnc.Futhm, intcua ahsin by PNAG anbifim-at ptins can b assum t b ita inan ninmnt such as th skin, h th bactiumxpincs cnsiab mchanica stss. Aitinay,th f PGA in smtanc94 suggsts an iginafunctin f this pym in th nn-infctius ifstyfS. epidermidis. M, n ca iffncs habn bs in th numb f MSCrAMMS fminfctius an cmmnsa stains fS. epidermidis, ini-cating that ths ptins a auab uing bth infc-tin an cnizatin. This maks sns, as ahsin thst tissu is cnsi t b impati uing bth
ifstys. S. epidermidis shu thf b gaas an accinta pathgn, th cinica imptanc fhich stms ss fm a icat infctius ifstyan m fm th fquncy f cntaminatin nts anth xistnc f mchanisms, such as ahsinan immun asin, that a bnficia f th bactiauing bth cnizatin an chnic infctin.
Antibiotic resistance and prophylaxis
Spcific antibitic sistanc gns a ispa inS. epidermidis. In many cuntis, incuing th UnitStats, 7590% f a hspita isats fS. epidermidis asistant t mthicillin, a fist-chic antibitic against sta-phyccca infctins; this is n high than th c-spning at f S. aureus (4060%)123. In sm cuntis,such as Th Nthans, fficint sach-an-stypgamms an stict hygin masus ha suc-c in kping th panc f mthiciin-sistantS. aureus in hspitas at a 124, has this haspn much ss succssfu f mthiciin-sistantS. epidermidis125. rsistanc t mthiciin is nc
n mobil gntic lmnts (MGes), namy th sta-phyccca casstt chmsm mec (SCCmec).This casstt chmsm cntains th mecA gn,hich ncs a pniciin-bining ptin, PBP2a,ith cas affinity f mthiciin cmpa ithth affinitis f th PBPs126. In S. epidermidis, 10 if-fnt SCCmec stuctus intifi; th shtSCCmec typ Iv mnt127 as th mst abunant(36%)128. SCCmec typ Iv pss a paticua pbm,as it s nt imps a fitnss cst t its hst an canthf spa in th absnc f scti antibiticpssu129. Intstingy, csy at stains can cayiffnt SCCmec typs, inicating that S. epidermidisfqunty ss an acquis SCCmec mnts128.
In aitin t mthiciin sistanc, S. epidermidisstains ha acqui sistanc t sa th antibit-ics, incuing ifamycin, fuquinns, gntamycin,ttacycin, champhnic, ythmycin, cinamy-cin an suphnamis5. rsistanc t stptgamins,inzi an tigcycin as ccus, athugh ay.Mst antibitic sistanc gns a pasmi-ncan a m ftn fun in mthiciin-sistant thanmthiciin-suscptib stains130. This is pbaby ut th fact that sistanc t mthiciin an th anti-bitics is fqunt amng nmic nscmia stains.Dspit ispa sistanc t mthiciin an thantibitics, 80% f cathts infct ith S. epidermidis
can sti b tat ith antibitics such as ancmycin,ithut catht ma131. H, intmiatsistanc t ancmycin has as bn scib132 anstaphyccca bifim fmatin significanty cassth actiity f ancmycin an th antibitics133135.
Th fquncy f antibitic sistanc in S. epider-midis fcts th us f antibitics. Futhm,th ubiquity fS. epidermidis as a human cmmnsamicganism ns this bactium an ptima caian si f antibitic sistanc gns, paticuayths that nt infict a maj fitnss cst t th bac-tium, such as SCCmec mnts. Accingy, th isinc suggsting that mthiciin sistanc casstts
Figure 6 |Staphylococcus epidermidis a a mma a ftu
mam. Determinants that are thought to contribute to both the colonization
and the pathogenesis ofS. epidermidis are shown, along with their functions. In animal
models, only the roles of poly-N-acetylglucosamine (PNAG; also known as PIA),
poly--glutamic acid (PGA) and the MSCRAMM (microbial surface componentrecognizing adhesive matrix molecule) SdrG in infection have been determined. Other
roles are based on in vitro experiments and environmental challenges during
colonization and infection. Regulators such as agror sigB are not shown; these control
many of the determinants shown and may therefore also have important functions
during both S. epidermidis lifestyles. AMP, antimicrobial peptide.
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tansf fm S. epidermidis t S. aureus128,136.Th acquisitin f SCCmec typ Iv by cmmunity-assciat mthiciin-sistant S. aureus (CA-MrSA)127may ha ha an nmus impact n pubic hath: itcat a stain ith bth mthiciin sistanc, at ncst t fitnss, an xcptina iunc, hich asth mcua basis bhin th pimic caus byCA-MrSA137. CA-MrSA as acqui th MGes thatmay b imptant f fficint cnizatin by hizntagn tansf fm S. epidermidis138. Ths finings shthat S. epidermidis pis a si functin f thtansf f gntic mnts t nhanc th pathgnicsuccss fS. aureus, an thf has an imptant in human isas.
Ths cnsiatins highight th n f p-phyactic masus against S. epidermidis infc-tins. vaccinatin an cnizatin, masus thata ftn iscuss f th pathgns incuingS. aureus, nt sm t b apppiat f S. epider-midis. Fist, th is n anti-staphyccca accinan sa ins f inc inicat that it may b
ifficut t us taitina acti immunizatin fstaphyccci 139,140. Scn, aicatin fS. epider-midis as a cmmn pat f th human micfa maynt ny b ifficut t achi, ing t th fact that-cnizatin fm th iniiuas is fast, but itmay as tun ut t b cuntpucti, as it maya ptntiay m hamfu micganisms ttak th pac fS. epidermidis. Thf, it is cm-mny ag that th bst ay t a ith S. epi-dermidis infctins is by pntin, hich incusstiizatin f mica quipmnt an f by patsf patints an ths hath ca psnn h ain cntact ith ining mica ics uingsugy5.
Unidirectional horizontal gene transfer?
Intstingy, athugh th is inc t suggstthat S. epidermidis can fqunty tansf MGes tS. aureus136,138, this tansf sms t b n ay: S. epi-dermidis s nt cntain txin gns, spit th factthat acquisitin f such gns f m S. aureus usinga simia mchanism u sm asy. Th cntinstigatin f cust guay intspac sht
painmic pat (CrISPr)squncs, sht patsthat ain in pnting th uptak f cnju-gati mnts such as phags an cnjugati pas-mis, may xpain hy th tansf f MGes btnS. epidermidis an S. aureus is uniictina141. Thssquncs ha bn fun in S. epidermidis, in nf th t gnm-squnc stains9, but nt inany f th many knn S. aureus gnms. CrISPr-miat pntin f MGe uptak in S. epidermidiscay ns t b futh auat, as this mcha-nism may psnt a mcua basis f th absncf a highy is txin pti an th sutingack f aggssi iunc in S. epidermidis.
Outlook
Kng abut th mcua mchanisms f bi-fim fmatin an thi guatin in S. epidermidisis amst xcusiy bas n in vitro sach. Thcntibutin f sm tminants such as PNAG5761,Ate142, SG44, SF47 an th guats agr83, luxS71an sigB143 t pathgnsis has bn mnstat
using anima ms. Futhm, th is incinicating that imptant bifim facts a xpssin vivo61,144. Nthss, th is an ugnt n fm tai in vivo sach that cu pi mch-anistic insight int S. epidermidis bifim-assciatinfctin. A cnty cnstuct biuminscnt stainf a bifim-fming cinica isat fS. epidermidismay b hpfu in ths naus145.
T auat ptntia n statgis t cmbatS. epidermidis infctins, n t btt un-stan th atinship btn th cmmnsa aninfctius ifstys f this bactium. T that n, shu m thughy instigat th tminantsthat nsu th suia fS. epidermidis in its natuahabitat; th pmnt f skin cnizatin msu b paticuay auab.
Finay, th intactin fS. epidermidis ith thbactia an its si functin f gns that canb tansf t S. aureus i n t b uciat inm tai. F sa f ths tasks, it u b hpfut tmin th gnm squncs f aitina S. epi-dermidis stains (paticuay ths f ST2) that sm tb mst iy istibut amng infctius isats15.
1. CDC. National Nosocomial Infections Surveillance
(NNIS) system report, data summary from January
1992 through June 2004, issued October 2004.Am.
J. Infect. Control32, 470485 (2004).2. Uckay, I. et al. Foreign body infections due to
Staphylococcus epidermidis.Ann. Med.41, 109119
(2009).
3. Dimick, J. B. et al. Increased resource use associated
with catheter-related bloodstream infection in the
surgical intensive care unit.Arch. Surg.136,
229234 (2001).
4. Rello, J. et al. Evaluation of outcome of intravenous
catheter-related infections in critically ill patients.Am.
J. Respir. Crit. Care Med.162, 10271030 (2000).
5. Rogers, K. L., Fey, P. D. & Rupp, M. E. Coagulase-
negative staphylococcal infections. Infect. Dis. Clin.
North Am.23, 7398 (2009).
This provides an excellent review on clinical aspects
of S. epidermidis infections.6. Costerton, J. W., Stewart, P. S. & Greenberg, E. P.
Bacterial biofilms: a common cause of persistent
infections. Science284, 13181322 (1999).
7. Kloos, W. & Schleifer, K. H. in Bergeys Manual of
Systematic Bacteriology (eds Sneath, P. H. A., Mair, N.,
Sharpe, M. E. & Holt, J. G.) 10131035 (Williams &
Wilkins, Baltimore, 1986).8. Kloos, W. E. & Musselwhite, M. S. Distribution and
persistence ofStaphylococcus and Micrococcus
species and other aerobic bacteria on human skin.
Appl. Microbiol.30, 381385 (1975).
9. Gill, S. R. et al. Insights on evolution of virulence
and resistance from the complete genome
analysis of an early methicillin-resistant
Staphylococcus aureus strain and a biofilm-
producing methicillin-resistant Staphylococcus
epidermidis strain.J. Bacter iol. 187,
24262438 (2005).
This article describes the sequencing and
comparison of the genomes of biofilm-forming
S. epidermidis and S. aureus.
10. Zhang, Y. Q. et al. Genome-based analysis of virulence
genes in a non-biofilm-forming Staphylococcus
epidermidis strain (ATCC 12228). Mol. Microbiol.49,
15771593 (2003).
11. Wang, X. M. et al. Evaluation of a multilocus sequence
typing system for Staphylococcus epidermidis.
J. Med. Microbiol.52, 989998 (2003).
12. Wisplinghoff, H. et al. Related clones containing SCCmectype IV predominate among clinically significant
Staphylococcus epidermidis isolates.Antimicrob. Agents
Chemother.47, 35743579 (2003).
13. Thomas, J. C. et al. Improved multilocus sequence
typing scheme for Staphylococcus epidermidis.J. Clin.
Microbiol.45, 616619 (2007).
14. Miragaia, M., Thomas, J. C., Couto, I., Enright, M. C.
& de Lencastre, H. Inferring a population structure
for Staphylococcus epidermidis from multilocus
sequence typing data.J. Bacteriol.189, 25402552
(2007).
This article details an investigation of the
population structure of S. epidermidis.
15. Li, M., Wang, X., Gao, Q. & Lu, Y. Molecular
characterization ofStaphylococcus epidermidis
strains isolated from a teaching hospital in
Shanghai, China.J. Med. Microbiol.58, 456461
(2009).
R E V I E W S
564 | AUGUST 2009 | volUMe 7 www.atu.m/vw/m
2009 Macmillan Publishers Limited. All rights reserved
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3242738&ordinalpos=12&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3242738&ordinalpos=12&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum7/28/2019 Staphylococcus Epidermidis Accidental Pathogen
11/13
16. Galdbart, J. O., Allignet, J., Tung, H. S., Ryden, C. & El
Solh, N. Screening for Staphylococcus epidermidis
markers discriminating between skin-flora strains and
those responsible for infections of joint prostheses.
J. Infect. Dis.182, 351355 (2000).
17. Gu, J. et al. Bacterial insertion sequence IS256as a
potential molecular marker to discriminate invasive
strains from commensal strains ofStaphylococcus
epidermidis.J. Hosp. Infect.61, 342348 (2005).18. Kozitskaya, S. et al. The bacterial insertion sequence
element IS256occurs preferentially in nosocomial
Staphylococcus epidermidis isolates: association withbiofilm formation and resistance to aminoglycosides.
Infect. Immun.72, 12101215 (2004).
19. Yao, Y. et al. Factors characterizing Staphylococcus
epidermidis invasiveness determined by comparative
genomics. Infect. Immun.73, 18561860 (2005).
20. Lina, G. et al. Bacterial competition for human nasal
cavity colonization: role of staphylococcal agralleles.
Appl. Environ. Microbiol.69, 1823 (2003).
21. OGrady, N. P. et al. Guidelines for the prevention of
intravascular catheter-related infections. MMWR
Recomm. Rep.51, 126 (2002).
22. Chu, V. H. et al. Coagulase-negative staphylococcal
prosthetic valve endocarditis a contemporary
update based on the International Collaboration on
Endocarditis: prospective cohort study. Heart95,
570576 (2009).
23. Massey, R. C., Horsburgh, M. J., Lina, G., Hook, M. &
Recker, M. The evolution and maintenance of virulence in
Staphylococcus aureus: a role for host-to-host
transmission? Nature Rev. Microbiol.4, 953958
(2006).
This article reviews the mathematical model that
explains the evolution of lifestyle differences
between S. epidermidis and S. aureus.
24. Otto, M., Sussmuth, R., Vuong, C., Jung, G. & Gotz, F.
Inhibition of virulence factor expression in
Staphylococcus aureus by the Staphylococcus
epidermidisagrpheromone and derivatives. FEBS
Lett.450, 257262 (1999).
25. Carmody, A. B. & Otto, M. Specificity grouping of the
accessory gene regulator quorum-sensing system of
Staphylococcus epidermidis is linked to infection.
Arch. Microbiol.181, 250253 (2004).
26. Harder, J. & Schroder, J. M. Antimicrobial peptides in
human skin. Chem. Immunol. Allergy86, 2241 (2005).27. Faurschou, M. & Borregaard, N. Neutrophil granules
and secretory vesicles in inflammation. Microbes
Infect.5, 13171327 (2003).
28. Pourmand, M. R., Clarke, S. R., Schuman, R. F., Mond,
J. J. & Foster, S. J. Identification of antigenic
components ofStaphylococcus epidermidis expressedduring human infection. Infect. Immun.74,
46444654 (2006).
29. Yao, Y., Sturdevant, D. E. & Otto, M. Genomewide
analysis of gene expression in Staphylococcus
epidermidisbiofilms: insights into the pathophysiology
of S. epidermidisbiofilms and the role of phenol-
soluble modulins in formation of biofilms.J. Infect.
Dis.191, 289298 (2005).
An investigation of genome-wide gene regulatory
changes that occur in S. epidermidis biofilms.
30. Khardori, N., Yassien, M. & Wilson, K. Tolerance of
Staphylococcus epidermidis grown from indwelling
vascular catheters to antimicrobial agents.J. Ind.
Microbiol.15, 148151 (1995).
31. Duguid, I. G., Evans, E., Brown, M. R. & Gilbert, P.
Effect of biofilm culture upon the susceptibility of
Staphylococcus epidermidis to tobramycin.
J. Antimicrobiol. Chemother.30, 803810 (1992).32. Duguid, I. G., Evans, E., Brown, M. R. & Gilbert, P.
Growth-rate-independent killing by ciprofloxacin ofbiofilm-derived Staphylococcus epidermidis; evidence
for cell-cycle dependency.J. Antimicrobiol. Chemother.
30, 791802 (1992).
33. OToole, G., Kaplan, H. B. & Kolter, R. Biofilm
formation as microbial development.Annu. Rev.
Microbiol.54, 4979 (2000).
34. Vacheethasanee, K. et al. Bacterial surface properties
of clinically isolated Staphylococcus epidermidis
strains determine adhesion on polyethylene.
J. Biomed. Mater. Res.42, 425432 (1998).
35. Heilmann, C., Hussain, M., Peters, G. & Gotz, F.
Evidence for autolysin-mediated primary attachment
ofStaphylococcus epidermidis to a polystyrene
surface. Mol. Microbiol.24, 10131024 (1997).
36. Tormo, M. A., Knecht, E., Gotz, F., Lasa, I. & Penades,
J. R. Bap-dependent biofilm formation by pathogenic
species ofStaphylococcus: evidence of horizontal gene
transfer? Microbiology151, 24652475 (2005).
37. Mazmanian, S. K., Liu, G., Ton-That, H. &
Schneewind, O. Staphylococcus aureus sortase, an
enzyme that anchors surface proteins to the cell wall.
Science285, 760763 (1999).
38. Navarre, W. W. & Schneewind, O. Surface proteins of
Gram-positive bacteria and mechanisms of their
targeting to the cell wall envelope. Microbiol. Mol.
Biol. Rev.63, 174229 (1999).
39. Arrecubieta, C., Lee, M. H., Macey, A., Foster, T. J. &
Lowy, F. D. SdrF, a Staphylococcus epidermidis
surface protein, binds type I collagen.J. Biol. Chem.
282, 1876718776 (2007).40. Hartford, O., OBrien, L., Schofield, K., Wells, J. &
Foster, T. J. The Fbe (SdrG) protein of
Staphylococcus epidermidis HB promotes bacterial
adherence to fibrinogen. Microbiology147,
25452552 (2001).
41. Heilmann, C. et al. Identification and characterization
of a novel autolysin (Aae) with adhesive properties
from Staphylococcus epidermidis. Microbiology149,
27692778 (2003).
42. McCrea, K. W. et al. The serine-aspartate repeat
(Sdr) protein family in Staphylococcus epidermidis.
Microbiology146, 15351546 (2000).
43. Nilsson, M. et al. A fibrinogen-binding protein of
Staphylococcus epidermidis. Infect. Immun.66,
26662673 (1998).
44. Guo, B., Zhao, X., Shi, Y., Zhu, D. & Zhang, Y.
Pathogenic implication of a fibrinogen-binding
protein ofStaphylococcus epidermidis in a rat model
of intravascular-catheter-associated infection. Infect.
Immun.75, 29912995 (2007).
45. Ponnuraj, K. et al. A dock, lock, and latch
structural model for a staphylococcal adhesin
binding to fibrinogen. Cell115, 217228 (2003).
This work elucidated the mechanism by which
SdrG binds to fibrinogen.46. Sellman, B. R. et al. Expression ofStaphylococcus
epidermidis SdrG increases following exposure to an
in vivo environment. Infect. Immun.76, 29502957
(2008).
47. Arrecubieta, C. et al. SdrF, a Staphylococcus
epidermidis surface protein, contributes to the
initiation of ventricular assist device driveline-related
infections. PLoS Pathog.5, e1000411 (2009).
48. Bowden, M. G. et al. Identification and preliminary
characterization of cell-wall-anchored proteins of
Staphylococcus epidermidis. Microbiology151,
14531464 (2005).
49. Gross, M., Cramton, S. E., Gotz, F. & Peschel, A. Key
role of teichoic acid net charge in Staphylococcus
aureus colonization of artificial surfaces. Infect.
Immun.69, 34233426 (2001).50. Sadovskaya, I., Vinogradov, E., Flahaut, S., Kogan, G.
& Jabbouri, S. Extracellular carbohydrate-containing
polymers of a model biofilm-producing strain,
Staphylococcus epidermidis RP62A. Infect. Immun.
73, 30073017 (2005).
51. Rice, K. C. et al. The cidA murein hydrolase regulator
contributes to DNA release and biofilm development
in Staphylococcus aureus. Proc. Natl Acad. Sci. USA
104, 81138118 (2007).
52. Mack, D. et al. The intercellular adhesin involved in
biofilm accumulation ofStaphylococcus epidermidis
is a linear -1,6-linked glucosaminoglycan:
purification and structural analysis.J. Bacteriol.
178, 175183 (1996).
This article details the structural characterization
of the exopolysaccharide PNAG.
53. Darby, C., Hsu, J. W., Ghori, N. & Falkow, S.
Caenorhabditis elegans: plague bacteria biofilm
blocks food intake. Nature417, 243244 (2002).
54. Wang, X., Preston, J. F. I. & Romeo, T. The pgaABCDlocus ofEscherichia colipromotes the synthesis of a
polysaccharide adhesin required for biofilm
formation.J. Bacteriol.186, 27242734 (2004).
55. Heilmann, C., Gerke, C., Perdreau-Remington, F. &
Gotz, F. Characterization of Tn917insertion mutants
ofStaphylococcus epidermidis affected in biofilm
formation. Infect. Immun.64, 277282 (1996).
56. Heilmann, C. et al. Molecular basis of intercellular
adhesion in the biofilm-forming Staphylococcus
epidermidis. Mol. Microbiol.20, 10831091
(1996).
This work identified the genetic locus that
governs PNAG biosynthesis.
57. Francois, P. et al. Lack of biofilm contribution to
bacterial colonisation in an experimental model of
foreign body infection by Staphylococcus aureus and
Staphylococcus epidermidis. FEMS Immunol. Med.
Microbiol.35, 135140 (2003).
58. Rupp, M. E., Ulphani, J . S., Fey, P. D., Bartscht, K. &
Mack, D. Characterization of the importance of
polysaccharide intercellular adhesin/hemagglutinin
ofStaphylococcus epidermidis in the pathogenesis
of biomaterial-based infection in a mouse foreign
body infection model. Infect. Immun.67,
26272632 (1999).
This was the firstin vivo analysis of an
S. epidermidis virulence determinant (PNAG)
using an isogenic mutant.
59. Rupp, M. E., Ulphani, J . S., Fey, P. D. & Mack, D.
Characterization ofStaphylococcus epidermidispolysaccharide intercellular adhesin/hemagglutinin
in the pathogenesis of intravascular catheter-
associated infection in a rat model. Infect. Immun.
67, 26562659 (1999).60. Chokr, A., Leterme, D., Watier, D. & Jabbouri, S.
Neither the presence ofica locus, nor in vitro-biofilm
formation ability is a crucial parameter for some
Staphylococcus epidermidis strains to maintain an
infection in a guinea pig tissue cage model. Microb.
Pathog.42, 9497 (2007).
61. Fluckiger, U. et al. Biofilm formation, icaADBC
transcription, and polysaccharide intercellular
adhesin synthesis by staphylococci in a device-
related infection model. Infect. Immun.73,
18111819 (2005).
62. Gerke, C., Kraft, A., Sussmuth, R., Schweitzer, O. &
Gotz, F. Characterization of the
N-acetylglucosaminyltransferase activity involved in
the biosynthesis of the Staphylococcus epidermidis
polysaccharide intercellular adhesin.J. Biol. Chem.
273, 1858618593 (1998).
This article describes the identification of the
biochemical function of the IcaA and IcaD
proteins.
63. Vuong, C. et al. A crucial role for exopolysaccharide
modification in bacterial biofilm formation, immune
evasion, and virulence.J. Biol. Chem.279,
5488154886 (2004).
This study identified the biochemical function of
the IcaB PNAG de-acetylase and showed its role
in vitro andin vivo.
64. OGara, J. P. ica and beyond: biofilm mechanisms
and regulation in Staphylococcus epidermidis and
Staphylococcus aureus. FEMS Microbiol. Lett.270,
179188 (2007).
65. Ziebuhr, W. et al. A novel mechanism of phase
variation of virulence in Staphylococcus epidermidis:
evidence for control of the polysaccharide
intercellular adhesin synthesis by alternating
insertion and excision of the insertion sequence
element IS256. Mol. Microbiol.32, 345356(1999).
66. Knobloch, J. K. et al. Biofilm formation by
Staphylococcus epidermidis depends on functional
RsbU, an activator of the sigB operon: differential
activation mechanisms due to ethanol and salt
stress.J. Bacteriol.183, 26242633
(2001).
67. Mack, D. et al. Identification of three essential
regulatory gene loci governing expression of
Staphylococcus epidermidis polysaccharide
intercellular adhesin and biofilm formation. Infect.
Immun.68, 37993807 (2000).
68. Tormo, M. A. et al. SarA is an essential positive
regulator ofStaphylococcus epidermidis biofilm
development.J. Bacteriol.187, 23482356
(2005).
69. Handke, L. D. et al.B and SarA independently
regulate polysaccharide intercellular adhesin
production in Staphylococcus epidermidis. Can.
J. Microbiol.53, 8291 (2007).70. Al Laham, N. et al. Augmented expression of
polysaccharide intercellular adhesin in a defined
Staphylococcus epidermidis mutant with the
small-colony-variant phenotype.J. Bacteriol.189,
44944501 (2007).71. Xu, L. et al. Role of the luxSquorum-sensing system
in biofilm formation and virulence of
Staphylococcus epidermidis. Infect. Immun.74,
488496 (2006).
72. Vuong, C., Gerke, C., Somerville, G. A., Fischer, E. R.
& Otto, M. Quorum-sensing control of biofilm factors
in Staphylococcus epidermidis.J. Infect. Dis.188,
706718 (2003).
73. Kogan, G., Sadovskaya, I., Chaignon, P., Chokr, A. &
Jabbouri, S. Biofilms of clinical strains of
Staphylococcus that do not contain polysaccharide
intercellular adhesin. FEMS Microbiol. Lett.255,
1116 (2006).
R E V I E W S
NATUre revIewS |Microbiology volUMe 7 | AUGUST 2009 |565
2009 Macmillan Publishers Limited. All rights reserved
7/28/2019 Staphylococcus Epidermidis Accidental Pathogen
12/13
74. Rohde, H. et al. Polysaccharide intercellular adhesin
or protein factors in biofilm accumulation of
Staphylococcus epidermidis and Staphylococcus
aureus isolated from prosthetic hip and knee joint
infections. Biomaterials28, 17111720 (2007).
This article gives an exceptionally balanced view
of the roles of proteins versus exopolysaccharide
in S. epidermis biofilm formation, in contrast to
several reports that point to the importance of
protein-mediated biofilm formation.75. Hussain, M., Herrmann, M., von Eiff, C., Perdreau-
Remington, F. & Peters, G. A 140-kilodaltonextracellular protein is essential for the accumulation
ofStaphylococcus epidermidis strains on surfaces.
Infect. Immun.65, 519524 (1997).
76. Rohde, H. et al. Induction ofStaphylococcus
epidermidisbiofilm formation via proteolytic
processing of the accumulation-associated protein by
staphylococcal and host proteases. Mol. Microbiol.
55, 18831895 (2005).
77. Conrady, D. G. et al. A zinc-dependent adhesion
module is responsible for intercellular adhesion in
staphylococcal biofilms. Proc. Natl Acad. Sci. USA
105, 1945619461 (2008).
This work shed light on the mechanism of Aap
self-aggregation.
78. Banner, M. A. et al. Localized tufts of fibrils on
Staphylococcus epidermidis NCTC 11047 are
comprised of the accumulation-associated protein.
J. Bacteriol.189, 27932804 (2007).79. Bateman, A., Holden, M. T. & Yeats, C. The G5
domain: a potential N-acetylglucosamine recognition
domain involved in biofilm formation. Bioinformatics
21, 13011303 (2005).
80. Sun, D., Accavitti, M. A. & Bryers, J. D. Inhibition of
biofilm formation by monoclonal antibodies against
Staphylococcus epidermidis RP62A accumulation-
associated protein. Clin. Diagn. Lab. Immunol.12,
93100 (2005).
81. Conlon, K. M., Humphreys, H. & OGara, J. P.
Inactivations ofrsbUand sarA by IS256represent
novel mechanisms of biofilm phenotypic variation in
Staphylococcus epidermidis.J. Bacteriol.186,
62086219 (2004).
82. Chaignon, P. et al. Susceptibility of staphylococcal
biofilms to enzymatic treatments depends on their
chemical composition.Appl. Microbiol. Biotechnol.
75, 125132 (2007).
83. Vuong, C., Kocianova, S., Yao, Y., Carmody, A. B. &
Otto, M. Increased colonization of indwelling medical
devices by quorum-sensing mutants ofStaphylococcus
epidermidisin vivo.J. Infect. Dis.190, 14981505
(2004).This manuscript shows the role of the S. epidermidis
agrquorum sensing regulatorin vivo.
84. Yarwood, J. M., Bartels, D. J., Volper, E. M. &
Greenberg, E. P. Quorum sensing in Staphylococcus
aureus biofilms.J. Bacteriol.186, 18381850
(2004).
85. Boles, B. R. & Horswill, A. R. Agr-mediated dispersal
ofStaphylococcus aureus biofilms. PLoS Pathog.4,
e1000052 (2008).
86. Teufel, P. & Gotz, F. Characterization of an extracellular
metalloprotease with elastase activity from
Staphylococcus epidermidis.J. Bacteriol.175,
42184224 (1993).
87. Dubin, G. et al. Molecular cloning and biochemical
characterisation of proteases from Staphylococcus
epidermidis. Biol. Chem.382, 15751582 (2001).
88. Ohara-Nemoto, Y. et al. Characterization and
molecular cloning of a glutamyl endopeptidase from
Staphylococcus epidermidis. Microb. Pathog.33,
3341 (2002).89. Kaplan, J. B. et al. Genes involved in the synthesis and
degradation of matrix polysaccharide inActinobacillus
actinomycetemcomitans andActinobacillus
pleuropneumoniae biofilms.J. Bacteriol.186,
82138220 (2004).90. Kaplan, J. B., Ragunath, C., Ramasubbu, N. & Fine,
D. H. Detachment ofActinobacillus
actinomycetemcomitans biofilm cells by an
endogenous -hexosaminidase activity.J. Bacteriol.
185, 46934698 (2003).
91. Kong, K. F., Vuong, C. & Otto, M. Staphylococcus
quorum sensing in biofilm formation and infection. Int.
J. Med. Microbiol.296, 133139 (2006).
92. Vuong, C. et al. Regulated expression of pathogen-
associated molecular pattern molecules in
Staphylococcus epidermidis: quorum-sensing determines
pro-inflammatory capacity and production of phenol-
soluble modulins. Cell. Microbiol.6, 753759 (2004).
93. Yao, Y. et al. Characterization of the Staphylococcus
epidermidis accessory-gene regulator response:
quorum-sensing regulation of resistance to human
innate host defence.J. Infect. Dis.193, 841848
(2006).
94. Kocianova, S. et al. Key role of poly--dl-glutamic acid
in immune evasion and virulence ofStaphylococcus
epidermidis.J. Clin. Invest.115, 688694 (2005).
This article investigates the role of
poly--dl-glutamic acid in S. epidermidis.
95. Little, S. F. & Ivins, B. E. Molecular pathogenesis of
Bacillus anthracis infection. Microbes Infect.1,131139 (1999).
96. Oppermann-Sanio, F. B. & Steinbuchel, A. Occurrence,
functions and biosynthesis of polyamides in
microorganisms and biotechnological production.
Naturwissenschaften 89, 1122 (2002).
97. Kristian, S. A. et al. Biofilm formation induces C3a
release and protects Staphylococcus epidermidis from
IgG and complement deposition and from neutrophil-
dependent killing.J. Infect. Dis.197, 10281035
(2008).
98. Vuong, C. et al. Polysaccharide intercellular adhesin
(PIA) protects Staphylococcus epidermidis against
major components of the human innate immune
system. Cell. Microbiol.6, 269275 (2004).
This study shows the important role of PNAG in
immune evasion.
99. Begun, J. et al. Staphylococcal biofilm
exopolysaccharide protects against Caenorhabditis
elegans immune defences. PLoS Pathog.3, e57
(2007).
100. Mah, T. F. et al. A genetic basis for Pseudomonas
aeruginosa biofilm antibiotic resistance. Nature426,
306310 (2003).
101. Heine, H. & Ulmer, A. J. Recognition of bacterial
products by Toll-like receptors. Chem. Immunol.
Allergy86, 99119 (2005).
102. Stevens, N. T. et al.Staphylococcus epidermidis
polysaccharide intercellular adhesin induces IL-8
expression in human astrocytes via a mechanism
involving TLR2. Cell. Microbiol.11, 421432 (2008).
103. Henneke, P. et al. Lipoproteins are critical TLR2
activating toxins in group B streptococcal sepsis.
J. Immunol.180, 61496158 (2008).
104. Li, H., Nooh, M. M., Kotb, M. & Re, F. Commercial
peptidoglycan preparations are contaminated with
superantigen-like activity that stimulates IL-17
production.J. Leukoc. Biol.83, 409418 (2008).
105. Hashimoto, M. et al. Not lipoteichoic acid but
lipoproteins appear to be the dominant
immunobiologically active compounds in
Staphylococcus aureus.J. Immunol.177,31623169 (2006).
106. Mehlin, C., Headley, C. M. & Klebanoff, S. J.
An inflammatory polypeptide complex from
Staphylococcus epidermidis: isolation and
characterization.J. Exp. Med.189, 907918 (1999).
This article describes the identification and
pro-inflammatory properties of the main
S. epidermidis PSMs.107. Wang, R. et al. Identification of novel cytolytic peptides
as key virulence determinants for community-
associated MRSA. Nature Med.13, 15101514
(2007).
108. Hajjar, A. M. et al. Cutting edge: functional
interactions between Toll-like receptor (TLR) 2 and
TLR1 or TLR6 in response to phenol-soluble modulin.
J. Immunol.166, 1519 (2001).
109. Lambert, P. A., Worthington, T., Tebbs, S. E. & El liott,
T. S. Lipid S, a novel Staphylococcus epidermidis
exocellular antigen with potential for the serodiagnosis
of infections. FEMS Immunol. Med. Microbiol.29,195202 (2000).
110. Li, M. et al. Gram-positive three-component
antimicrobial peptide-sensing system. Proc. Natl
Acad. Sci. USA104, 94699474 (2007).
This work identified and characterized the first
Gram-positive AMP sensor in S. epidermidis.
111. Peschel, A. et al. Inactivation of the dltoperon in
Staphylococcus aureus confers sensitivity to
defensins, protegrins, and other antimicrobial
peptides.J. Biol. Chem.274, 84058410 (1999).
112. Peschel, A. et al.Staphylococcus aureus resistance to
human defensins and evasion of neutrophil killing via
the novel virulence factor MprF is based on
modification of membrane lipids with l-lysine.J. Exp.
Med.193, 10671076 (2001).
113. Li, M. et al. The antimicrobial peptide-sensing system
aps ofStaphylococcus aureus. Mol. Microbiol.66,
11361147 (2007).
114. Bader, M. W. et al. Recognition of antimicrobial
peptides by a bacterial sensor kinase. Cell122,
461472 (2005).
115. Marin, M. E., de la Rosa, M. C. & Cornejo, I.
Enterotoxigenicity ofStaphylococcus strains isolated
from Spanish dry-cured hams.Appl. Environ.
Microbiol.58, 10671069 (1992).
116. Bautista, L., Gaya, P., Medina, M. & Nunez, M.
A quantitative study of enterotoxin production by
sheep milk staphylococci.Appl. Environ. Microbiol.
54, 566569 (1988).
117. Klingenberg, C. et al. Persistent strains of coagulase-negative staphylococci in a neonatal intensive care
unit: virulence factors and invasiveness. Clin.
Microbiol. Infect.13, 11001111 (2007).
118. Scheifele, D. W., Bjornson, G. L., Dyer, R. A. &
Dimmick, J. E. Delta-like toxin produced by coagulase-
negative staphylococci is associated with neonatal
necrotizing enterocolitis. Infect. Immun.55,
22682273 (1987).
119. Rohde, H. et al. Detection of virulence-associated
genes not useful for discriminating between invasive
and commensal Staphylococcus epidermidis strains
from a bone marrow transplant unit.J. Clin. Microbiol.
42, 56145619 (2004).
120. Ziebuhr, W. et al. Modulation of the polysaccharide
intercellular adhesin (PIA) expression in biofilm
forming Staphylococcus epidermidis. Analysis of
genetic mechanisms.Adv. Exp. Med. Biol.485,
151157 (2000).
121. Rogers, K. L., Rupp, M. E. & Fey, P. D. The presence of
icaADBCis detrimental to the colonization of human
skin by Staphylococcus epidermidis.Appl. Environ.
Microbiol.74, 61556157 (2008).
122. Lai, Y. et al. The human anionic antimicrobial peptide
dermcidin induces proteolytic defence mechanisms in
staphylococci. Mol. Microbiol.63, 497506 (2007).
123. Diekema, D. J. et al. Survey of infections due to
Staphylococcus species: frequency of occurrence and
antimicrobial susceptibility of isolates collected in the
United States, Canada, Latin America, Europe, and the
Western Pacific region for the SENTRY Antimicrobial
Surveillance Program, 19971999. Clin. Infect. Dis.
32 , S114S132 (2001).
124.Vos, M. C., Ott, A. & Verbrugh, H. A. Successful
search-and-destroy policy for methicillin-resistant
Staphylococcus aureus in The Netherlands.J. Clin.
Microbiol.43, 2034; author reply 20342035
(2005).
125. van Pelt, C. et al. Strict infection control measures do
not prevent clonal spread of coagulase negative
staphylococci colonizing central venous catheters in
neutropenic hemato-oncologic patients. FEMSImmunol. Med. Microbiol.38, 153158 (2003).
126. Chambers, H. F., Hartman, B. J. & Tomasz, A.
Increased amounts of a novel penicillin-binding protein
in a strain of methicillin-resistant Staphylococcus
aureus exposed to nafcillin.J. Clin. Invest.76,
325331 (1985).
127. Ma, X. X. et al. Novel type of staphylococcal cassette
chromosome mec identified in community-acquired
methicillin-resistant Staphylococcus aureus strains.
Antimicrob. Agents Chemother.46, 11471152
(2002).128. Miragaia, M., Couto, I. & de Lencastre, H. Genetic
diversity among methicillin-resistant Staphylococcus
epidermidis (MRSE). Microb. Drug Resist.11, 8393
(2005).
129. Diep, B. A. et al. The arginine catabolic mobile
element and staphylococcal chromosomal cassette
mec linkage: convergence of virulence and resistance
in the USA300 clone of methicillin-resistant
Staphylococcus aureus.J. Infect. Dis.197,15231530 (2008).
130. Miragaia, M. et al. Molecular characterization of
methicillin-resistant Staphylococcus epidermidis
clones: evidence of geographic dissemination.J. Clin.
Microbiol.40, 430438 (2002).
131. Raad, I., Hanna, H. & Maki, D. Intravascular catheter-
related infections: advances in diagnosis, prevention,
and management. Lancet Infect. Dis.7, 645657
(2007).
132. Schwalbe, R. S., Stapleton, J. T. & Gilligan, P. H.
Emergence of vancomycin resistance in coagulase-
negative staphylococci. N. Engl. J. Med.316,
927931 (1987).
133. Gagnon, R. F., Richards, G. K. & Subang, R.
Vancomycin therapy of experimental peritoneal
catheter-associated infection (Staphylococcus
epidermidis) in a mouse model. Perit. Dial. Int.13
(Suppl. 2), 310312 (1993).
R E V I E W S
566 | AUGUST 2009 | volUMe 7 www.atu.m/vw/m
2009 Macmillan Publishers Limited. All rights reserved
7/28/2019 Staphylococcus Epidermidis Accidental Pathogen
13/13
134. Richards, G. K., Prentis, J. & Gagnon, R. F. Antibiotic
activity against Staphylococcus epidermidis biofilms in
dialysis fluids.Adv. Perit. Dial.5, 133137
(1989).
135. Raad, I. et al. Comparative activities of daptomycin,
linezolid, and tigecycline against catheter-related
methicillin-resistant Staphylococcus bacteremic
isolates embedded in biofilm.Antimicrob. Agents
Chemother.51, 16561660 (2007).136. Hanssen, A. M., Kjeldsen, G. & Sollid, J. U. Local
variants of staphylococcal cassette chromosome mec
in sporadic methicillin-resistant Staphylococcusaureus and methicillin-resistant coagulase-negative
staphylococci: evidence of horizontal gene transfer?
Antimicrob. Agents Chemother.48, 285296 (2004).
137. Chambers, H. F. The changing epidemiology of
Staphylococcus aureus? Emerg. Infect. Dis.7,
178182 (2001).
138. Diep, B. A. et al. Complete genome sequence of
USA300, an epidemic clone of community-acquired
meticillin-resistant Staphylococcus aureus. Lancet
367, 731739 (2006).
139. DeLeo, F. R. & Otto, M. An antidote for
Staphylococcus aureus pneumonia?J. Exp. Med.
205, 271274 (2008).
140. Otto, M. Targeted immunotherapy for staphylococcal
infections: focus on anti-MSCRAMM antibodies.
BioDrugs22, 2736 (2008).
141. Marraffini, L. A. & Sontheimer, E. J. CRISPR
interference limits horizontal gene transfer in
staphylococci by targeting DNA. Science322,
18431845 (2008).
This article describes the functional characterization
of CRISPR sequences in S. epidermidis.
142. Rupp, M. E., Fey, P. D., Heilmann, C. & Gotz, F.
Characterization of the importance ofStaphylococcus
epidermidisautolysin and polysaccharide intercellular
adhesin in the pathogenesis of intravascular catheter-
associated infection in a rat model.J. Infect. Dis.183,
10381042 (2001).143. Pintens, V. et al. The role ofB in persistence of
Staphylococcus epidermidis foreign body infection.
Microbiology154, 28272836 (2008).
144.Vandecasteele, S. J., Peetermans, W. E., Merckx, R. &
Van Eldere, J. Expression of biofilm-associated genes
in Staphylococcus epidermidis during in vitro and
in vivo foreign body infections.J. Infect. Dis.188,
730737 (2003).
145.Vuong, C., Kocianova, S., Yu, J., Kadurugamuwa, J. L.
& Otto, M. Development of real-time in vivo imaging
of device-related Staphylococcus epidermidis infection
in mice and influence of animal immune status on
susceptibility to infection.J. Infect. Dis.198,
258261 (2008).
146. Novick, R. P. & Geisinger, E. Quorum sensing in
staphylococci.Annu. Rev. Genet.42, 541564
(2008).147. Novick, R. P. et al. Synthesis of staphylococcal
virulence factors is controlled by a regulatory RNA
molecule. EMBO J.12, 39673975 (1993).148. Queck, S. Y. et al. RNAIII-independent target gene
control by the agrquorum-sensing system: insight into
the evolution of virulence regulation in Staphylococcus
aureus. Mol. Cell32, 150158 (2008).149. Mayville, P. et al. Structureactivity analysis of
synthetic autoinducing thiolactone peptides from
Staphylococcus aureus responsible for virulence. Proc.
Natl Acad. Sci. USA96, 12181223 (1999).
150. Otto, M., Sussmuth, R., Jung, G. & Gotz, F. Structure
of the pheromone peptide of the Staphylococcus
epidermidisagrsystem. FEBS Lett.424, 8994
(1998).
151. Otto, M. Staphylococcus aureus and Staphylococcus
epidermidis peptide pheromones produced by the
accessory gene regulator agrsystem. Peptides22,
16031608 (2001).
152. Otto, M., Echner, H., Voelter, W. & Gotz, F. Pheromone
cross-inhibition between Staphylococcus aureus and
Staphylococcus epidermidis. Infect. Immun.69,
19571960 (2001).
153.Vuong, C., Gotz, F. & Otto, M. Construction and
characterization of an agrdeletion mutant of
Staphylococcus epidermidis. Infect. Immun.68,
10481053 (2000).
154. Simons, J. W. et al. Cloning, purification and
characterisation of the lipase from Staphylococcus
epidermidis comparison of the substrate selectivity
with those of other microbial lipases. Eur. J. Biochem.
253, 675683 (1998).
155. Farrell, A. M., Foster, T. J. & Holland, K. T. Molecular
analysis and expression of the lipase of
Staphylococcus epidermidis.J. Gen. Microbiol.139,
267277 (1993).
156. Longshaw, C. M., Farrell, A. M., Wright, J. D. &
Holland, K. T. Identification of a second lipase gene,
gehD, in Staphylococcus epidermidis: comparison of
sequence with those of other staphylococcal lipases.
Microbiology146, 14191427 (2000).157. Lindsay, J. A., Riley, T. V. & Mee, B. J. Production of
siderophore by coagulase-negative staphylococci and
its relation to virulence. Eur. J. Clin. Microbiol. Infect.
Dis.13, 10631066 (1994).
158. Cotton, J. L., Tao, J. & Balibar, C. J. Identi fication and
characterization of the Staphylococcus aureus gene
cluster coding for staphyloferrin A. Biochemistry48,
10251035 (2009).
159. Cockayne, A. et al. Molecular cloning of a
32-kilodalton lipoprotein component of a novel iron-regulated Staphylococcus epidermidis ABC
transporter. Infect. Immun.66, 37673774 (1998).
160. Chamberlain, N. R. & Brueggemann, S. A.
Characterisation and expression of fatty acid modifying
enzyme produced by Staphylococcus epidermidis.
J. Med. Microbiol.46, 693697 (1997).
161. Park, P. W., Rosenbloom, J., Abrams, W. R.,
Rosenbloom, J. & Mecham, R. P. Molecular cloning
and expression of the gene for elastin-binding protein
(ebpS) in Staphylococcus aureus.J. Biol. Chem.271,
1580315809 (1996).
AcknowledgementsThis work was supported by the intramural research pro-
gramme of the National Institute of Allergy and Infectious
Diseases.
DATABASESEntrez Gene:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehld |luxS|mecA
Entrez Genome Project:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genomeprj
Bacillus anthracis | Caenorhabditis elegans | Escherichia coli |
Pseudomonas aeruginosa|Staphylococcus aureus |
S. epidermidis ATCC 12228 | S. epidermidis RP62A |Yersinia
pestis
UniProtKB:http://www.uniprot.org
-toxin | Aap | AtlE | GraR | GraS|IcaA | IcaB |IcaC|IcaD |MprF| SdrF | SdrG | SdrH | TLR2
FURTHER INFORMATIONMichael Ottos homepage:http://www3.niaid.nih.gov/labs/
aboutlabs/lhbp/pathogenMolecularGeneticsSection/otto.htm
All links Are AcTiVe in The online PdF
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