Staphylococcus Epidermidis Accidental Pathogen

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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.

R E V I E W S


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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.

R E V I E W S


http://www.uniprot.org/uniprot/Q9L470http://www.uniprot.org/uniprot/Q2FWM8http://www.uniprot.org/uniprot/Q2FWM8http://www.uniprot.org/uniprot/Q2FWM8http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12333http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12333http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12333http://www.uniprot.org/uniprot/Q2FWM8http://www.uniprot.org/uniprot/Q9L470


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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.

R E V I E W S


http://www.ncbi.nlm.nih.gov/sites/entrez?Db=genomeprj&cmd=ShowDetailView&TermToSearch=9548http://www.ncbi.nlm.nih.gov/sites/entrez?Db=genomeprj&cmd=ShowDetailView&TermToSearch=9548http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12339http://www.uniprot.org/uniprot/O60603http://www.uniprot.org/uniprot/O60603http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12339http://www.ncbi.nlm.nih.gov/sites/entrez?Db=genomeprj&cmd=ShowDetailView&TermToSearch=9548http://www.ncbi.nlm.nih.gov/sites/entrez?Db=genomeprj&cmd=ShowDetailView&TermToSearch=9548


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+ ++ +

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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.

R E V I E W S


http://www.uniprot.org/uniprot/Q5HPI1http://www.uniprot.org/uniprot/Q8CTL4http://www.uniprot.org/uniprot/Q5HR81http://www.uniprot.org/uniprot/Q5HR81http://www.uniprot.org/uniprot/Q8CTL4http://www.uniprot.org/uniprot/Q5HPI1


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Colonization

Mechanical resistance (biofilm)

Immune evasion and AMPs



Osmoprotection

Adhesion to tissue

Pathogenesis

Mechanical resistance (biofilm)

Immune evasion, AMPs,immunoglobulins,

complement and phagocytosis

Immune evasion, AMPsand phagocytosis


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.

R E V I E W S


http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3242263&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3242263&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


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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.

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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

R E V I E W S
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3240443&ordinalpos=10&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_RVDocSumhttp://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_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3242263&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3242263&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genomeprjhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genomeprjhttp://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12333http://www.ncbi.nlm.nih.gov/sites/entrez?Db=genomeprj&cmd=ShowDetailView&TermToSearch=9548http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12319http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12339http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12339http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12304http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12304http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=search&term=txid176280%5borgn%5dhttp://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=search&term=txid176280%5borgn%5dhttp://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=search&term=txid176279%5borgn%5dhttp://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=search&term=txid176279%5borgn%5dhttp://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12303http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12303http://www.ncbi.nlm.nih.gov/sites/entrez?db=genomeprj&cmd=Retrieve&dopt=Overview&list_uids=12303http://www.uniprot.org/http://www.uniprot.org/http://www.uniprot.org/uniprot/Q2FWM8http://www.uniprot.org/uniprot/Q2FWM8http://www.uniprot.org/uniprot/Q9L470http://www.uniprot.org/uniprot/O33635http://www.uniprot.org/uniprot/Q5HR81http://www.uniprot.org/uniprot/Q8CTL4http://www.uniprot.org/uniprot/Q8CTL4http://www.uniprot.org/uniprot/Q8GLC5http://www.uniprot.org/uniprot/Q8GLC5http://www.uniprot.org/uniprot/Q6TYB1http://www.uniprot.org/uniprot/P69518http://www.uniprot.org/uniprot/P69518http://www.uniprot.org/uniprot/P69518http://www.uniprot.org/uniprot/P69519http://www.uniprot.org/uniprot/P6

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