Myeloid C-Type Lectin Receptors in Viral Recognition and Antiviral Immunity

22 Pages·2017·2.2 MB·English

viruses
Review
Myeloid C-Type Lectin Receptors in Viral
Recognition and Antiviral Immunity
JoãoT.MonteiroandBerndLepenies*
UniversityofVeterinaryMedicineHannover,ImmunologyUnit&ResearchCenterforEmergingInfectionsand
Zoonoses(RIZ),Bünteweg17,30559Hannover,Germany;[email protected]
* Correspondence:[email protected];Tel.:[phone]
AcademicEditor:BarryR.O’Keefe
Received:18November2016;Accepted:17March2017;Published:22March2017
Abstract: Recognitionofviralglycansbypatternrecognitionreceptors(PRRs)ininnateimmunity
contributestoantiviralimmuneresponses.C-typelectinreceptors(CLRs)arePRRscapableofsensing
glycans present in viral pathogens to activate antiviral immune responses such as phagocytosis,
antigenprocessingandpresentation,andsubsequentTcellactivation. TheabilityofCLRstoelicit
andshapeadaptiveimmunityplaysacriticalroleintheinhibitionofviralspreadwithinthehost.
However,certainvirusesexploitCLRsforviralentryintohosTcellstoavoidimmunerecognition.
To block CLR interactions with viral glycoproteins, antiviral strategies may involve the use of
multivalentglycancarriersystems. Inthisreview,wedescribetheroleofCLRsinantiviralimmunity
andwehighlighttheirdualfunctioninviralclearanceandexploitationbyviralpathogens.
Keywords: C-type lectin receptors; glycans; dendritic cells; macrophages; immunomodulation;
antiviralimmunity;viralevasion
1. Introduction
Theimmunesystemisahostdefensesystemcomposedofcellularandhumoralcomponents
withtheabilitytoprotectthehostagainstpathogens,foreignsubstancesandtissuedamage[1]. Itcan
besubdividedintoinnateimmunity[2]andadaptiveimmunity[3]. Recognitionofevolutionarily
conserved pathogen-derived ligands, so-called pathogen-associated molecular patterns (PAMPs),
bythehostinnateimmunesystemismediatedbypatternrecognitionreceptors(PRRs). PRRsare
essential to initiate innate responses and also contribute to the induction of adaptive immune
responses [4,5]. Major classes of PRRs comprise Toll-like receptors (TLRs) [6], nucleotide-binding
oligomerizationdomains(NOD)-likereceptors(NLRs)[7],retinoicacid-induciblegene(RIG)-I-like
receptors(RLRs)[8],DNAsensors[9],andC-typelectinreceptors(CLRs)[10].
Myeloid CLRs in innate immunity are glycan-binding receptors that are specialized in the
recognition of glycolipids and glycoproteins present on pathogens and also on hosT cells [10–12].
Since numerous pathogens including bacteria, parasites, fungi, and viruses are coated by glycans,
glycanrecognitionbyhostCLRsisvitaltoelicitimmuneresponses. CLRsmayimpactimmunityat
severallevels,rangingfromphagocytosistotheproductionofeffectorcytokinesandchemokines[13].
Moreover, various CLRs act as endocytic receptors on antigen-presenting cells (APCs), thus are
involvedintheuptakeofpathogensforantigenprocessingandpresentation,andsubsequentTcell
activation[14].
TheroleofCLRsinviralrecognitioniscomplex. CLRsexpressedbyAPCs,suchasdendritic
cells(DCs)andmacrophages,areabletorecognizeandquicklyrespondtoabroadrangeofviruses
inordertoshapeantiviralimmuneresponses. However,someviruseshaveevolvedmechanismsto
exploitCLRstotriggercellentry,todisruptsignalingpathwaysinthecell,ortoinhibitAPCeffector
functions[15].
Viruses2017,9,59;doi:10.3390/v9030059 www.mdpi.com/journal/viruses
Viruses2017,9,59 2of22
Inthisreview,wedescribetheintricateinterplaybetweenvirusesandCLRsandhighlightthe
roleofCLRsinantiviralimmunityaswellastheirexploitationbyviralpathogensforimmuneevasion.
2. ViralGlycoproteins—EssentialComponentsforViralInteractionswithHosTcells
Glycosylation is a highly diverse process that produces an abundant and highly regulated
repertoireofcomplexglycansthatarecovalentlyattachedtoproteinsandlipidspresentonthesurface
ofhosTcellsandviruses. IncontrasttoDNAandproteinbiosynthesis,thebiosynthesisofglycans
isnotatemplate-drivenprocess. Instead,itreliesonanorchestratedactionofglycosyltransferases
andglycosidasesthatarepresentintheendoplasmicreticulum(ER)andtheGolginetwork[16,17].
Two major types of glycan structures are linked to proteins: N-linked glycans and O-linked
glycans. N-glycosylationischaracterizedbytheattachmentofN-acetylglucosamine(GlcNAc)and
mannose residues to the amide nitrogen of an asparagine residue in the context of the conserved
motif Asn-X-Ser/Thr. A complex process of trimming and remodeling of the oligosaccharide by
glycosyltransferasesandglycosidases,firstintheERandlaterintheGolgiapparatus,finallyleads
totheformationofN-glycansoftheoligomannosetype,thecomplextype,orthehybridtype[18].
Allsubtypesshareacommonpentasaccharidecore,wheretheoligomannosetypepossessessolely
mannose residues attached to the core, while the complex type has antennae initiated by GlcNAc
attached to the pentasaccharide core, and the hybrid type comprises both mannose and GlcNAc
attachments [17,19]. O-glycosylation takes place once the protein has transited to the Golgi and
carbohydratesarelinkedcovalentlyviaglycosidiclinkagesfromserineorthreonineresidues. Highly
branchedglycanstructurescanbeachievedbyO-glycosylationsinceeachmonosaccharidehasseveral
hydroxylgroupsforlinkageandcanformglycosidicbondsinanαorβconfiguration[20].
AcommonglycanmodificationatterminalendsofN-andO-linkedglycans,aswellasglycolipids,
istheattachmentofacidicsugarstermedsialicacids. Sialicacidsarepresentintheoutermostend
ofglycanchainsofallcellsurfaceglycansinhighervertebrates[21]. Inhumans,themostcommon
sialic acid is α5-N-acetylneuraminic acid (Neu5Ac) and derivatives of this nine-carbon backbone
carbohydrateintodifferentsialicacidvariantscanoccurbychemicalmodifications,suchasacetylation,
methylationandsulfation[21,22]. Sialicacidsarenegativelychargedmoleculesthatareinvolvedin
celladhesion,signalingeventstoelicitimmuneresponsesandkeyrecognizedstructuresbyseveral
virusesandbacteria[23].
Virusesasobligatoryintracellularpathogenshijackandbenefitfromthehostcellglycosylation
machinery [24]. Glycosylation of viral surface proteins takes place upon viral replication inside
hosT cells and it is often essential to maintain the stability of these proteins and viral particles.
Moreover,glycanmoietiesinviralglycoproteinsareresponsibleforadelicateinterplaybetweenviruses
andhosTcellsthroughspecificinteractionswithlectinspresentonthesurfaceofhosTcells[24,25].
Particularly,N-linkedhighmannosetypeglycansareoftenessentialforbiologicalfunctionsofviral
glycoproteins,suchasstabilityandantigenicity,anditmayalsoimpactbindingofvirusestohostcell
receptorsandsubsequentinternalization[26]. Indeed,glycoproteinspresentinenvelopedvirusessuch
asthehumanimmunodeficiencyvirus1(HIV-1),Ebolavirus(EBOV),WestNilevirus(WNV),Nipah
virus,Newcastlevirus,andSARScoronavirus(SARS-CoV)wereshowntohaveN-linkedglycansthat
arecrucialforproteinfolding,viralinfectivity,andimmuneevasion(reviewedin[26]). Forinstance,
inhepatitisCvirus(HCV),theglycosylationpatternsofenvelopeglycoproteinshaveadualroleas
theycontributetoviralentryintohosTcellsontheonehand,andensureproperproteinfoldingand
maturationontheotherhand[27]. Consistently,mutagenesisinglycosylationsitesoftheHCVE1
proteinaffectedtranslocationoftheproteintotheviralsurfaceandthusreducedinfectivity[28].
Althoughviralglycosylationisintrinsicallyconnectedtothehostduetohijackingofthehost
glycosylationmachinery,theglycosylationprofilesofvirusesandhosTcellsmaydiffer,sinceviral
glycoproteins are often more heavily glycosylated and present different glycan modifications [24].
Thegp120glycoproteinoftheHIV-1enveloperepresentsameaningfulexample,asgp120comprises
more than 20 N-linked glycan moieties and is one of the heaviest N-glycosylated proteins in
Viruses2017,9,59 3of22
nature. IncontrasttomammalianglycoproteinsthatoftendisplaycomplextypeN-glycans,gp120
predominantlycarriesoligomannoseN-glycansduetoahinderedprocessingofglycanintermediates
byERandGolginetworkglycoenzymes[29].
The crucial role of viral glycosylation in the biology of infection has prompted research on
glycan-bindingreceptors(so-calledlectins)onhostimmunecellsthatarecapableofrecognizingglycan
structuresonvirusesandelicitingimmuneresponses,notablyalectinsuperfamilytermedCLRs.
3. MyeloidC-typeLectinsReceptors—PatternRecognitionReceptorsinInnateImmunity
CLRsarecarbohydrate-bindingproteinsthatpossessaC-typelectin-likedomain(CTLD)[30],
a conserved structural motif arranged as two protein loops stabilized by two disulfide bridges at
the base of each loop [31]. This key structural motif in CLRs is responsible for the recognition of
avarietyofligands,ofteninaCa2+-dependentfashionthroughacompactmoduletermedcarbohydrate
recognitiondomain(CRD)[12]. AlthoughmostCLRsbindtoglycoconjugates,theymayalsorecognize
non-carbohydrate ligands such as cholesterol [32] and uric acid crystals [33]. Specific amino acid
motifswithintheCRDconferligandspecificitytoCLRssuchastheEPN(Glu-Pro-Asn)motifandthe
QPD(Gln-Pro-Asp)motifthatpredeterminebindingaffinitytowardsmannose/fucoseandgalactose
residues, respectively [30]. The CLR superfamily is the largest and most diverse lectin family in
animalsandhasbeenclassifiedinto17groups(I-XVII)basedonphylogeny,structural,andfunctional
properties [31]. This review focuses on myeloid CLRs that are predominantly expressed by APCs
such as monocytes, macrophages, and DCs. APCs have a pivotal role in pathogen uptake and
antigenpresentationtonaïveTcellsoneithermajorhistocompatibilitycomplex(MHC)-IorMHC-II
molecules[34,35]. Recognitionofpathogen-derivedglycansbyCLRsonAPCscontributescriticallyto
theseAPCfunctions[36]. Inaddition,CLRengagementtriggerscytokineandchemokinesecretion,
whichisnecessarytoshapeadaptiveimmuneresponses[36].
TherespectivemyeloidCLRsbelongtogroupII,V,andVI,accordingtotheabove-mentioned
classification. GroupIIiscomposedoftypeIItransmembraneCLRs,suchasthedendriticcell-specific
intercellularadhesionmolecule-3-grabbingnonintegrin(DC-SIGN),andtheDC-immunoreceptor
(DCIR), which contain a short cytoplasmic tail, a transmembrane domain, an extracellular stalk
region and a Ca2+-dependent CRD [13,31]. Dependent on the length of the stalk region, different
oligomerizationstatesmayoccurinmembersofthisgroup. CLRsingroupVinclude,forexample,
themyeloidDAP-12associatinglectin(MDL-1)andDectin-1thatpossessashortcytoplasmictail,
atransmembranedomainandanextracellularstalkregionfollowedbyasingleCTLDoftenlacking
typicalCa2+orcarbohydratesbindingsites[13,31].GroupVICLRsaretypeItransmembranereceptors
withanextracellulardomainencompassingaN-terminalricin-likedomain,afibronectintype2domain
andeighttotenCTLDs[13,31]. ProminentCLRssuchasthemacrophagemannosereceptor(MMR)
andDEC-205belongtothelattergroup.
Myeloid CLRs may have intracellular signaling motifs and—based on the presence of these
motifs—are classified into four main groups: immunoreceptor tyrosine-based activating motif
(ITAM)-bearing CLRs, hemi-ITAM (hemITAM)-bearing CLRs, immunoreceptor tyrosine-based
inhibitory motif (ITIM)-bearing CLRs, and a group of CLRs lacking typical signaling motifs
(Figure 1) [13,37]. ITAMs consist of YxxL/I tandem repeats and are present in ITAM-bearing
adaptorproteinssuchastheFcRγchain. CLRssuchastheDC-associatedC-typelectin(Dectin)-2,
DC-immunoactivatingreceptor(DCAR),macrophageinducibleC-typelectin(Mincle),andMDL-1
belong to this group of ITAM-bearing CLRs. An intracellular hemITAM motif (a single YxxL/I
sequence) is found in CLRs such as Dectin-1, C-type lectin domain family (CLEC)-2, CLEC-9A,
and SIGN-R3. Generally, CLRs that carry a hemITAM motif or are associated with ITAM-bearing
adaptorproteinsactivatethespleentyrosinekinase(SYK)[38]. SYKactivationpromptstheformation
ofaternarycomplexinvolvingtheadaptorproteinscaspaserecruitmentdomain-containingprotein9
(CARD9),mucosa-associatedlymphoidtissuelymphomatranslocationprotein1(MALT1),andB-cell
lymphoma/leukemia10(BCL10),whichtriggerstheactivationofthetranscriptionfactornuclearfactor
Viruses 2017, 9, 59   4 of 21 
(CARD9), mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and B‐
Viruses2017,9,59 4of22
cell lymphoma/leukemia 10 (BCL10), which triggers the activation of the transcription factor nuclear 
factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) [13,38] and other transcription factors 
ksuapchp aa-lsi gthhte- cnhauicnle-eanrh faancctoerr ooffa catcitviavtaetdedB Tce lclsel(lNs F(N-κFBA)[T1)3 ,a3n8d]a nacdtiovtahteorr trparnostceriinp 1ti o(nAfPa‐c1t)o r[s13su].c hThaes 
tahcetinvuatciloenar offa ctthoersoef saicgtnivaalitnedg Tcacseclalsd(eNs FiAn TA)PanCds auclttiivmataotrelpyr oleteaidns1 t(oA cPy-t1o)k[1in3e]. pTrhoedauccttivioanti oanndo fTth ceeslel 
spirginmailningg [c3a6s]c. aIdne csoinntAraPsCt, sITuIltMim‐baetealryinlega CdsLtRosc syutockhi naes pthroed DuCct iiomnmanudnoTrceeclelpptroirm (iDngC[I3R6)], .CInLEcoCn‐t1r2aAst,, 
IaTnIdM C-bLeEaCri‐n1g2BC mLRays sinuhchibaits ctehlleuDlaCr riemspmounnsoesr etcherpotuogrh( DthCeI rRe)c,rCuLitEmCe-n1t2 oAf ,tyanrodsiCnLe EpCh-o1s2pBhamtaasyeisn, hsuibciht 
caesl lSurlca rhroemspoolongsyes rtehgriooung 2h dthoemraeicnr‐uciotnmtaeinntinogf tpyhroossipnheaptahsoes p(ShHatPa)s‐e1s ,asnudc hSHasP‐S2r c[1h3o,3m9]o. loTghye rfeoguirotnh 
2grdooump aoifn C-cLoRnst aiinncilnugdepsh mosepmhbaetarsse w(iStHhoPu)t- 1knanowdnS HITPA-2M[s1 3o,r3 9IT].IMThs,e sfuocuhr tahs tghreo uMpMoRf,C DLERCs‐i2n0c5l,u adneds 
mDCem‐SbIGerNsw thitahto aurtek innovwolnveITdA inM esnodroIcTyItMossi,ss, uthchusa scothnetrMibMutRe ,tDo EanCt-i2g0e5n, apnrodcDesCs-iSnIgG aNndth parteasreenitnavtioolnve tdo 
iTn ecnedllos cy[3t6o]s.i s,CtLhRus  ecnongtargibeumteentot abnyt iggelyncparnosc epssriensgenatn dinp rveisreanl tagtliyocnotporTotceeinllss [o36ft]e.nC LleRaednsg atog evmireunst 
binytegrlnyacalinzsatpiorens iennttoi nAPviCras.l glycoproteinsoftenleadstovirusinternalizationintoAPCs.

Figure 1. Recognition of pathogen-associated molecular patterns (PAMPs), damage-associated
Figure  1.  Recognition  of  pathogen‐associated  molecular  patterns  (PAMPs),  damage‐associated 
molecular patterns (DAMPs) and signaling motifs of myeloid C-type lectin receptors (CLRs).
molecular patterns (DAMPs) and signaling motifs of myeloid C‐type lectin receptors (CLRs). CLRs 
CLRs expressed by antigen-presenting cells (APCs) are able to recognize PAMPs present on
expressed by antigen‐presenting cells (APCs) are able to recognize PAMPs present on pathogens, 
pathogens, including bacteria, viruses, fungi and parasites; and DAMPs in damaged hosT cells.
including bacteria, viruses, fungi and parasites; and DAMPs in damaged host cells. Recognized 
Recognized ligands cover a vast type of glycan structures, such as fucose, mannose, β-glucan,
ligands cover a vast type of glycan structures, such as fucose, mannose, β‐glucan, galactose, GlcNAc, 
galactose,GlcNAc,butalsonon-glycanligandssuchasmonosodiumurate.UponCLRengagement,
but also non‐glycan ligands such as monosodium urate. Upon CLR engagement, a signaling cascade 
a signaling cascade is initiated through binding of early adaptors and the recruitment of kinases
is initiated through binding of early adaptors and the recruitment of kinases or phosphatases. 
or phosphatases. Myeloid CLRs can be subdivided in four distinct groups according to their
Myeloid CLRs can be subdivided in four distinct groups according to their cytoplasmic signaling 
cytoplasmicsignalingmotifsandearlyadaptors:(A)hemi-immunoreceptortyrosine-basedactivating
motifs and early adaptors: (A) hemi‐immunoreceptor tyrosine‐based activating motif (hemITAM)‐
motif(hemITAM)-coupled;(B)ITAM-coupled;(C)immunoreceptortyrosine-basedinhibitorymotif
coupled; (B) ITAM‐coupled; (C) immunoreceptor tyrosine‐based inhibitory motif (ITIM)‐coupled; 
(ITIM)-coupled;and(D)ITAM-ITIMindependentCLRs.
and (D) ITAM‐ITIM independent CLRs. 
Processing of viral proteins in endosomal compartments finally results in the presentation of
a ntigen-derivedpeptidesonMHC-IImoleculestonaïveCD4+Tcells(Figure2). Importantly,CLRs
Viruses 2017, 9, 59   5 of 21 
VirusesP2r0o1c7e,9s,s5in9g of viral proteins in endosomal compartments finally results in the presentatio5nof o22f 
antigen‐derived peptides on MHC‐II molecules to naïve CD4+ T cells (Figure 2). Importantly, CLRs 
are also involved in cross‐presentation, thus linking the endocytosis of viral pathogens with the 
are also involved in cross-presentation, thus linking the endocytosis of viral pathogens with the
pprreesseennttaattiioonn ooff vviirraall ppeeppttiiddeess oonn MMHHCC-‐II mmoolleeccuulleess ttoo aaccttiivvaattee CCDD88++ TT cceellllss.. IInn aaddddiittiioonn,, ssiiggnnaalliinngg 
cascades triggered by CLR/virus interactions induce the expression of co‐stimulatory molecules and 
cascadestriggeredbyCLR/virusinteractionsinducetheexpressionofco-stimulatorymoleculesand
the production of cytokines, therefore contributing to the fate determination of naïve T cells upon 
theproductionofcytokines, thereforecontributingtothefatedeterminationofnaïveTcellsupon
activation [40,41]. Thus, CLRs are at the frontline of innate and adaptive antiviral immune responses. 
activation[40,41]. Thus,CLRsareatthefrontlineofinnateandadaptiveantiviralimmuneresponses.
In the following sections, the role of selected CLRs in viral recognition and antiviral immune 
Inthefollowingsections,theroleofselectedCLRsinviralrecognitionandantiviralimmuneresponses
responses will be described. 
willbedescribed.

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aaccttiivvaattiioonn aanndd ssuubbsseeqquueenntt TT cceellll ssttiimmuullaattiioonn.. UUppoonn bbiinnddiinngg,, eennddooccyyttoossiiss wwiillll ttaakkee ppllaaccee,, rreessuullttiinngg iinn tthhee 
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mforoleefcfiuclieens tfoprr iemffiincgieonft CpDri4m+inangd oCf CDD8+4+T acnedll sC,rDe8sp+ eTc ctievlelsly, .reTswpoecstiigvneallys. aTrweroe qsiuginreadlsf oarreT rceeqlulaircetidv afotiro Tn 
cbeyllD aCctsi.vFaitrisotn,t hbye TD-cCesll. rFeicrestp, ttohre( TTC‐cRe)llr erecocegpntiozer s(TMCHRC) /repceopgtindiezecso mMpHleCx/epse.pSteicdoen cdo,mthpelceoxsetsi.m Suelcaotnordy, 
tmhoe lceocustliemsuClDat8o0r/yC mDo8l6ecinutleersa CctDw8i0th/CCDD8268 inexteprraecsts weditbhy CthDe2T8 ecxepll.reInssaeddd biyti othne, DTC cselelx. Ipnr easdsdaintidonse, cDreCtes 
ecyxptorkeisnse asn.dT hseeccroemteb ciyntaotkioinneosf. Tthhees ecosmignbainlsatdioetne romf tihneesset hsiegfnaatelso dfettheermacitnivesa ttehde Tfactee lol.f the activated T 
cell. 
3.1. DC-SIGN
3.1. DC‐SIGN 
Human DC-SIGN, encoded by the CD209 gene, is composed of a short cytoplasmic tail,
atranHsummemanb rDanCe‐SrIeGgiNo,n ,eancfloedxeibdl ebnye cthked oCmDa2i0n9 ingveonlev, eids icnoomlipgoosmeder iozfa tai osnh,oarnt dcaytCopa2l+as-dmeipce tnadile, nat 
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ptrlaancselo[4c5a]ti.oInn toefr aDctCios ntob estewcoenendaDryC slyamnpdhToicde lolsrgisanfas cwilihtaetreed abnytigthene ipnrteesreancttiaotniono ftDo CT- ScIeGllNs twakitehs 
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isnpteecricfieclliutylafro radhhigehsiomna nmnoolseecuglley c(aICnAs Man)d‐3f uocno steh-ec oTn taceinlli nsgurgflayccea n[4s3(]e. .gD.,CL‐SeIwGiNs apnrtiegseennsts) [l4ig3a,4n6d]. 
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abveirdeictoyg tnoi zgelydcboycoDnCju-gSaIGteNs ,pirnecsleundti nogn HpaIVth-o1,gEeBnsO [V4,3H]. CNVu,mdeenroguues evnirvueslo(DpeVd), vciyrtuosmese gwaelorev irreupso(rCteMdV to), 
bane dreScAoRgnSi-zCeodV b[y4 4D,4C7–‐S4I9G].NT,h ienlcelvuedlinogf DHCI-VS‐I1G, NEBeOxpVr,e sHsiCoVn,d deteenrgmuien evsirvuisru (sDcVap), tucyreto,minedgicaalotevdirbuys 
(aCmMoVre), eaffincdi eSnAtHRSIV‐C-1oVbi n[4d4in,4g7–b4y9D]. CTsh(ec hleavraecl teorfi zDeCd‐bSyIGaNh igexhpDreCs-sSioIGn Ndeetxeprmreisnseiosn v)icroums pcaapretdurteo, 
other cell types expressing DC-SIGN in low abundance [50]. Since glycosylation patterns of viral
Viruses2017,9,59 6of22
glycoproteins are governed by the glycosylation machinery of the hosT cells in which the virus
replicates,thisstronglyaffectstheDC-SIGNabilitytorecognizeandbindtodifferentiallyglycosylated
virusessuchasHIV-1andEBOV[51,52]. DC-SIGNmediatescaptureandfurthertransferofHIV-1to
Tcells(Figure3)[53,54]. DC-SIGN-mediatedHIV-1infectionoccursinDCsthatthentransportvirions
from sites of HIV-1 exposure, such as the mucosal membranes or bloodstream, to CD4+ T cells in
lymphoidtissues[55]. DC-SIGNrecognizeshigh-mannoseoligosaccharidesonthegp120moleculeof
HIVVir-u1s,esa 2g01l7y, c9o, 5p9r o teinpresentintheouterlayerofthevirusessentialforviralentryintohosTc7e lolfs 2[14 2].
UponDC-SIGNcaptureofHIV-1,mostofthevirionsaretransportedtotheproteasome,assistedbythe
In this study, an endocytosis‐defective mutant of L‐SIGN was still capable of facilitating viral 
interactionofthecytoskeletalphosphoproteinlymphocyte-specificprotein1(LSP1),wherelysosomal
infection, highlighting the role of L‐SIGN as an attachment factor for phlebobviruses, whereas  
degradationtakesplace. FurtherantigenprocessingandpresentationtheninducesprimingofTcells.
DC‐SIGN acted as an authentic entry receptor [72]. Another study indicated DC‐SIGN and L‐SIGN 
Moreover, DC-SIGN engagement by HIV-1 activates a signaling cascade that ultimately triggers
as authentic endocytic receptors for influenza A virus (IAV) entry and infection [73]. Sialic acid‐
Raf-1activationtomodulatecytokineresponsesbyNF-κBactivation. However,HIV-1iscapableof
deficient Chinese hamster ovary cell lines were resistant to IAV infection, but pH‐ and dynamin‐
exploitingtheDC-SIGNsignalingcascadeinordertoenhancetranscriptionoftheHIV-1genomeby
dependent  infectivity  was  restored  by  expression  of  DC‐SIGN/L‐SIGN.  Upon  expression  of 
NF-κB-mediatedexpression[56]. Anotherexploitationmechanismencompassestheabilityofintact
endocytosis‐defective DC‐SIGN/L‐SIGN, IAV was still bound by the cells, but susceptibility to 
DC-SIGN-boundHIV-1virionsofbeingnon-fusogenicallyinternalizedintonon-lysosomalendosomes,
infection was clearly reduced [73]. 
whereCstoalbleilcittiyvealnyd, Li‐nSfIeGcNtiv aintyd oDfCth‐SeIGviNri ownesrere smhoawinni ntot aacctt feoitrhseerv aesr aatltadcahymse[5n7t ]f.acIttoisrsn footre vwirourstehsy otrh at
HIaVs -a1udtheegnrtaidc aetnitorny roerceppetrosriss tiennvcoelviends iidne mDeCmsb,raasnew feulslioans.D HCe-nmcee, dthiaetye drevpirreusesnttr atanrsgmetiss sfoior nvitrousCeDs 4+
Tctoel hlsi,jaiscks tcreollnuglalyr fduenpcetinodnesn itn oonrdthere tNo -egvlaydceo simylmatuionne pdreofefinleseosf agnpd1 s2p0re[5a8d] .infection. 

Figure 3. Human immunodeficiency virus type 1 (HIV‐1) capture and transmission by DCs. Dendritic 
Figure3.Humanimmunodeficiencyvirustype1(HIV-1)captureandtransmissionbyDCs.Dendritic
cell‐specific intercellular adhesion molecule‐3‐grabbing non integrin (DC‐SIGN) present at the surface 
cell-specificintercellularadhesionmolecule-3-grabbingnonintegrin(DC-SIGN)presentatthesurface
of DCs neutralizes HIV‐1 by virion uptake and signalosome‐mediated cytokine production and 
of DCs neutralizes HIV-1 by virion uptake and signalosome-mediated cytokine production and
degradation of virions. Fragmented peptides are loaded on MHC class II molecules for antigen 
degradation of virions. Fragmented peptides are loaded on MHC class II molecules for antigen
presentation to CD4+ T cells in order to prime T cell effector functions and induce an adaptive immune 
presentation to CD4+ T cells in order to prime T cell effector functions and induce an adaptive
response against the virus. DC‐SIGN establishment of a DC‐T‐cell interaction is accomplished 
immuneresponseagainstthevirus.DC-SIGNestablishmentofaDC-T-cellinteractionisaccomplished
through transient binding to intercellular adhesion molecule (ICAM)‐3. However, DC‐SIGN is also 
through transient binding to intercellular adhesion molecule (ICAM)-3. However, DC-SIGN is
exploited by HIV‐1 for evasion of the immune response by maintenance of intact virions in non‐
also exploited by HIV-1 for evasion of the immune response by maintenance of intact virions in
lysosomal endosomes. These virions undergo exocytosis and can infect CD4+ T cells in a process called 
non-lysosomalendosomes.ThesevirionsundergoexocytosisandcaninfectCD4+Tcellsinaprocess
trans‐infection. Trans‐infection can also occur without HIV‐1 virion internalization. Additional 
calledtrans-infection.Trans-infectioncanalsooccurwithoutHIV-1virioninternalization.Additional
subversion strategies of HIV‐1 encompass augmented viral replication via the DC‐SIGN signalosome 
subversionstrategiesofHIV-1encompassaugmentedviralreplicationviatheDC-SIGNsignalosome
and triggering of DC apoptosis via apoptosis signal‐regulating kinase 1 (ASK‐1). 
andtriggeringofDCapoptosisviaapoptosissignal-regulatingkinase1(ASK-1).
3.3. LSECtin 
Liver and lymph node sinusoidal endothelial cell C‐type lectin (LSECtin, or CLEC4G) is located 
on chromosome 19p13.3 in humans, together with DC‐SIGN and L‐SIGN [74]. LSECtin shares a 31% 
and 32% amino acid sequence homology with DC‐SIGN and L‐SIGN, respectively, and is expressed 
by liver, lymph node and bone marrow sinusoidal endothelial cells, and by Kupffer cells in the 
liver [74,75]. LSECtin was reported to recognize glycans containing mannose, N‐acetylglucosamine 
(GlcNAc) and fucose residues [75].
Viruses2017,9,59 7of22
AfterovercomingdegradationinDCs,HIV-1virionscanbetransferredtoCD4+Tcellsthrough
the“infectioussynapse”inareplication-independentprocesstermedtrans-infection[59]. Inmature
DCs,protectionofHIV-1virionsfromendocytosisoccurstoagreaterextentcomparedtoimmature
DCs[60]. HIV-1-boundDC-SIGNalsodampenstheexpressionofCD86andMHC-IImolecules,thus
affecting antiviral immune responses and facilitating trans-infection [61]. In a recent study, it was
shownthatligationofDC-SIGNbygp120sensitizesDCstoundergoacceleratedapoptosisinresponse
to a variety of stimuli, mediated by excessive activation of the pro-apoptotic molecule apoptosis
signal-regulatingkinase1(ASK-1)[62].
3.2. L-SIGN
Lymphnode-specificintercellularadhesionmolecule-3-grabbingintegrin(L-SIGN,alsonamed
DC-SIGNR)isaCLRsimilartoDC-SIGN,exhibitinga77%aminoacidsequenceidentityandasimilar
protein architecture [44]. As DC-SIGN, L-SIGN is a type II transmembrane protein with a short
cytoplasmictailinvolvedinsignalingandinternalization,atransmembraneregion,aneckdomain
consisting of eight repeat regions of 23 amino acids, and a Ca2+-dependent CRD [63]. Oppositely
to DC-SIGN, L-SIGN presents a highly variable and polymorphic neck region, which impacts
ligand-binding affinity and specificity for viral pathogens [40,44]. The neck region of L-SIGN is
essential for tetramerization, thus increasing the binding avidity to multivalent ligands displayed
on pathogen surfaces [44]. L-SIGN expression is restricted to endothelial cells present in lymph
nodes,placenta,andliversinusoidalendothelialcells[63]. L-SIGNbindstoN-linkedhigh-mannose
oligosaccharides,withabindingpreferenceformannosylatedresidues[44]. IncontrasttoDC-SIGN,
L-SIGN does not bind to blood group antigens [44]. L-SIGN is involved in the recognition and
capture of glycan structures present on a variety of pathogens, including bacteria, viruses, fungi
andparasites[44]. SimilartoDC-SIGN,L-SIGNisalsoexploitedbyseveralviruses,suchasHIV-1,
EBOV, HCV, hepatitis B virus (HBV), Sindbis virus, SARS-CoV, and Marburg virus (MARV) for
glycoprotein-mediatedattachmentandinternalization[64–70].
Furthermore, WNV, a flavivirus with two viral surface glycoproteins (protein E and prM/M),
was shown to bind to L-SIGN with a higher affinity compared to DC-SIGN, resulting in host cell
infectivity[71]. Légeretal.dissectedthedifferencesintheinteractionsofphleboviruses,including
RiftValleyfevervirus(RVFV),Toscanavirus,andUukuniemiviruswithDC-SIGNandL-SIGN[72].
Inthisstudy,anendocytosis-defectivemutantofL-SIGNwasstillcapableoffacilitatingviralinfection,
highlightingtheroleofL-SIGNasanattachmentfactorforphlebobviruses,whereasDC-SIGNactedas
anauthenticentryreceptor[72]. AnotherstudyindicatedDC-SIGNandL-SIGNasauthenticendocytic
receptorsforinfluenzaAvirus(IAV)entryandinfection[73]. Sialicacid-deficientChinesehamster
ovarycelllineswereresistanttoIAVinfection,butpH-anddynamin-dependentinfectivitywasrestored
byexpressionofDC-SIGN/L-SIGN.Uponexpressionofendocytosis-defectiveDC-SIGN/L-SIGN,IAV
wasstillboundbythecells,butsusceptibilitytoinfectionwasclearlyreduced[73]. Collectively,L-SIGN
andDC-SIGNwereshowntoacteitherasattachmentfactorsforvirusesorasauthenticentryreceptors
involvedinmembranefusion. Hence,theyrepresenttargetsforvirusestohijackcellularfunctionsin
ordertoevadeimmunedefensesandspreadinfection.
3.3. LSECtin
LiverandlymphnodesinusoidalendothelialcellC-typelectin(LSECtin,orCLEC4G)islocatedon
chromosome19p13.3inhumans,togetherwithDC-SIGNandL-SIGN[74]. LSECtinsharesa31%and
32%aminoacidsequencehomologywithDC-SIGNandL-SIGN,respectively,andisexpressedbyliver,
lymphnodeandbonemarrowsinusoidalendothelialcells,andbyKupffercellsintheliver[74,75].
LSECtinwasreportedtorecognizeglycanscontainingmannose,N-acetylglucosamine(GlcNAc)and
fucoseresidues[75].
LSECtin was discovered to enhance EBOV and SARS-CoV infection, however, in contrast to
DC-SIGNandL-SIGN,didnotimpactHIV-1andHCVinfection[76]. Moreover,viralinteractions
Viruses2017,9,59 8of22
withLSECtinwerenotcompetitivelyinhibitedbythemannose-containingpolysaccharidemannan
suggesting that this CLR recognizes a more restricted spectrum of viruses presumably in
a mannose-independent manner [77]. Similarities between LSECtin and DC-SIGN/L-SIGN in
viral recognition range from the expression of this CLR by endothelial cells to the interaction
with viral glycoproteins and the subsequent endocytosis of bound ligands [77]. The cytoplasmic
domainofLSECtincomprisesatyrosinemotifanddiglutamic-containingmotifsthatmediateEBOV
internalizationthroughLSECtin. Thus,LSECtin,suchasDC-SIGN,mightfunctionasavirusuptake
receptor[78].However,incontrasttoDC-SIGN/L-SIGN,LSECtin-ligandcomplexesarenotdissociated
byalowpHmilieu,indicatingadifferentialintracellulartraffickinguponendocytosis[77].
LSECtinwasdescribedtoregulateintrahepaticTcellimmunityandtolimitliverinjuryinamodel
ofinducedexperimentalacutehepatitis[79,80]. UsingLSECtin-deficientmiceinadenovirusinfection
and HBV replication as murine models for viral hepatitis, Liu et al. demonstrated that LSECtin
facilitatedthereductionofliverinflammationbydelayingvirusclearanceandthatthisprocesscould
behijackedbyvirusesasanimmuneevasionmechanism[81].
3.4. Langerin
Langerhans cells (LCs) are a distinct subset of DCs that can be found in the epidermis and
oropharyngealmucosaandareeffectiveAPCscapableofinducingTcellresponses[82]. LCsexpress
arepertoireofPRRs,includingTLRsandCLRs. TheCLRlangerinisatypeIItransmembraneprotein
thathasaproline-richshortintracellularcytoplasmicdomainandanextracellulardomainconsisting
ofaneck-regionthatformshomo-trimers[83,84]. AlthoughlangerinisuniquelyexpressedbyLCs
in humans, langerin-positive dermal DCs in mice were also identified [85]. Oligomerization into
threeidenticalCRDshomo-trimers),enablestoincreaseligandavidityandaffectsthecarbohydrate
specificityoflangerin[84]. TheCRDoflangerincontainsanEPNmotifanditwasshownthatlangerin
binds to mannose, fucose, and GlcNAc in a Ca2+-dependent manner [84]. Notably, interaction of
langerinwithβ-glucanwasrecentlyshown, hencediversifyingtheligandprofileofthisCLR[86].
Amongotherpathogens,langerinrecognizesvirusessuchasHIV-1andmeaslesvirus(MV)[85,87].
LangerinplaysanimportantroleinantiviralresponsesinimmatureLCsbycapturingHIV-1for
degradationinBirbeckgranules[85,88]. IncontrasttoDC-SIGNthatcontributestoHIV-1spreadby
trans-infectionofTcells,langerinhasaprotectiveroleduringHIV-1infectionbydampeningvirus
spread[85,88]. HIV-1infectionofLCsoccurswhenlangerinfunctionisimpairedorincaseofhigh
viraltiters. Thus,inhibitionoflangerinenablesHIV-1infectionofLCsandfacilitatesfurthervirus
transmissiontoTcells[88,89].
MV,amemberofthegenusMorbillivirusinthefamilyParamyxoviridae,isahighlycontagious
virusthatentersthehostviatherespiratorytractandhasatropismforlymphocytesandmyeloidcells.
LangerinwasshowntobeareceptorforMV,althoughitdoesnotmediatevirusentryintohosTcells
directly. Langerin may rather be involved in immunity to MV as both immature and mature LCs
efficientlypresentedMV-derivedantigenstoCD4+Tcells[90]. Recently,langerinwasshowntobean
authenticreceptorforbindingandinternalizationofIAVleadingtoincreasedviralinfection[91].
3.5. DendriticCellImmunoreceptor
TheDCimmunoreceptor(DCIR,alsoknownasC-typelectinsuperfamily6,CLECSF6)isatypeII
transmembraneproteinthatcontainsanintracellularITIMandcomprisesanunusualsequenceinits
CRD,wheretheclassicalEPNmotifismodifiedbysubstitutionoftheasparaginebyaserineresidue
resultinginanEPS(Glu-Pro-Ser)motif[92]. HumanDCIRispredominantlyexpressedbycellsofthe
myeloidlineage,suchasDCs,macrophages,neutrophils,andmonocytes[93]. Theglycanspecificity
ofhumanDCIRincludesfucose-andmannose-containingglycans,asdemonstratedbybindingto
mannotrioseandLewisb[94]. TheroleofDCIRinimmunityisnotyetcompletelyunderstood,butit
maybeinvolvedintheregulationofDCexpansion[95],antigenprocessing,andantigenpresentation
forefficientCD4+andCD8+Tcellpriming[96,97]. KnowledgeaboutDCIRduringinfectionsisstillat
Viruses2017,9,59 9of22
itsinfancy;however,ithasbeenreportedthathumanDCIRrecognizesHIV-1[98–100]. MurineDCIR
impactstheimmuneresponseduringChikungunyavirus(CHIKV)infection[101],butmayalsobe
involvedinimmunepathologyduringparasiteinfections,asshownforcerebralmalaria[102].
HumanDCIRactsasanattachmentfactorforHIV-1onDCsandsurfaceexpressionofDCIRby
CD4+ TcellsisinducedbyHIV-1[92,93,98,99]. ThisincreasedexpressionofDCIRbyCD4+ Tcells
enhancesHIV-1attachment, viralentry, replicationandtransfer, finallyresultinginahighervirus
dissemination[93,99].
CHIKV, an arthropod-borne virus of the Alphavirus genus in the family Togaviridae, causes
rheumatic disease in humans characterized by inflammation and damage of musculoskeletal
tissues[101]. ConsistentwiththeroleofDCIRasaninhibitoryCLR,DCIR-/- miceexhibitedmore
severediseasecomparedtowild-typecontrolmicefollowingCHIKVinfection. Diseaseexacerbation
inDCIR-/-miceincludedamorerapidandmoresevereonsetofvirus-inducededemaandenhanced
weightloss,increasedinflammationanddamageinboththefasciaoftheinoculatedfootandtheankle
joint,aswellasanalteredcytokineresponse[101]. Thisstudysuggestsaprotectiveroleformurine
DCIRinlimitingCHIKV-inducedinflammation.
3.6. MDL-1
The myeloid DAP-12-associating lectin (MDL-1, also known as CLEC5A) is a type II
transmembranereceptorthatismainlyexpressedbymonocytes,macrophagesandneutrophils,but
not by monocyte-derived DCs [103,104]. The short cytoplasmic domain of MDL-1 interacts with
theITAM-bearingtransmembraneadaptorDAP-12(12-kDaDNAX-activatingprotein), leadingto
phosphorylationandsubsequentsignalingviatheSykkinase[38,103,105]. MDL-1doesnotpossess
afullsetofCa2+-coordinatingandcarbohydrate-bindingsitesandexhibitsahomodimericstructureat
thecellsurface[106,107]. Glycanbindingspecificitystillremainsunknown[106]. Uptonow,MDL-1
was shown to recognize several viral pathogens, including DV [108], Japanese encephalitis virus
(JEV)[109],andinfluenzaviruses[110].
DV, a mosquito-borne virus of the family Flaviviridae, is the causative agent of dengue fever.
InfectionswithDVmayleadtothedevelopmentofdenguehemorrhagicfeveranddengueshock
syndrome[111]. MDL-1wasshowntobindtoDVandtoactivateasignalingcascadeaccompanied
bythereleaseofpro-inflammatorycytokines[108,112]contributingtopathophysiologicalchanges
in DV-infected patients [113]. Upon DV recognition by MDL-1, DAP-12 becomes phosphorylated
leadingtoSykactivation.Subsequentinductionofthepro-inflammatorycytokinesIL-1βandIL-18and
activationoftheNLRP3(NACHT,LRRandPYDdomains-containingprotein3)inflammasomeand
caspase-1triggercelldeath(pyroptosis)[114].Moreover,DVactivatesnuclearfactor(erythroid-derived
2)-like 2 (Nrf2) in murine mononuclear phagocytes to enhance tumor necrosis factor (TNF)-α
productionthroughupregulationofMDL-1[115]. Antibody-mediatedMDL-1blockadeattenuated
theproductionofpro-inflammatorycytokinesbyDV-infectedmacrophages,suggestingthatMDL-1
targetingcanbeameanstoamelioratetissuedamage[108].
MDL-1isalsoessentialinosteoclastogenesisandboneremodelinguponassociationwithboth
DAP-12 and DAP-10 in bone marrow-derived osteoclasts [116]. Osteoclasts are multinucleated
gianT cells that differentiate from macrophages and are involved in bone remodeling [116].
DVinfectionofosteoclastswasrecentlyshowntoupregulateosteolyticactivity[117]. Attenuationof
DV-inducedosteolyticactivitywasobservedinMDL-1-/- miceand,consistently,administrationof
aMDL-1antagonistinwild-typemicealsoinhibitedDV-activatedosteolyticactivity[117].
JEVwasshowntobindtoMDL-1andtoinduceDAP-12phosphorylationinmacrophagesas
well. Antibody-mediatedMDL-1blockadeinhibitedJEV-inducedpro-inflammatorycytokinerelease
from microglia and prevented bystander damage to neuronal cells. In addition, treatment with
ananti-MDL-1antibodyreducedtheinfiltrationofJEV-harboringleukocytesintothecentralnervous
system, attenuated neuroinflammation, and decreased JEV-induced lethality in mice [109]. Thus,
Viruses2017,9,59 10of22
MDL-1playsacriticalroleinthepathogenesisofJapaneseencephalitisandmayrepresentapromising
targetforthedevelopmentofnewtreatments[109].
In a recent study, MDL-1 was demonstrated to interact with the hemagglutinin (HA) protein
of influenza viruses [110]. Two modes of interaction can take place between IAV and lectins:
calcium-dependentbindingoflectinstotheviralglycoproteins,andbindingofviralHAtosialylated
carbohydratesonthelectin(thisbindingmodemainlyoccursinsolublelectins)[25].SinceMDL-1does
notcomprisethecanonicalsetofcalciumcoordinatingandcarbohydratebindingsites,ligandbinding
mayoccurinaCa2+-independentfashion[106].InadditiontoidentifyingMDL-1asanIAV-recognizing
lectin, this study highlighted that antibody-mediated MDL-1 blockade or MDL-1 silencing led to
decreased levels of pro-inflammatory cytokines produced by human macrophages. Consistently,
MDL-1-/- mice exhibited reduced levels of pro-inflammatory cytokines, decreased immune cell
infiltration in the lungs and improved survival compared to wild-type mice indicating a crucial
roleforMDL-1ininflammatoryresponses,thuscontributingtoinfluenzapathogenicity[110].
3.7. MacrophageMannoseReceptor
TheMMRisaCLRexpressedbymonocyte-derivedDCs,dermalDCs,macrophages,andhepatic
endothelialcells. Itisinvolvedininnateimmunitybyrecognitionofglycanstructuresonpathogensas
wellinhomeostasisbyclearanceofthepituitaryhormoneslutropinandthyrotropin[118]. MMRis
capable of recognizing mannose, fucose, and GlcNAc residues that are abundant on the envelope
glycoproteinsofvariousviruses.MMRcomprehendsanN-terminalcysteine-richdomain,afibronectin
type II domain, and eight CRDs that bind and release ligands at the low pH environment within
endolysosomesinaCa2+-dependentmanner.MMRcandimerize;atcellsurfacesthereisanequilibrium
between the monomeric and dimeric form [119]. MMR interacts with a wide range of pathogens,
includingvirusessuchasHIV-1,butalsobindstofungi,bacteria,andparasites[118]. TheMMRis
involvedinthephagocytosisofpathogensandisinternalizedintotheendosomalsystemuponligand
bindingviaclathrin-coatedvesicles[120].
MMRwasshowntobindtotheHIVenvelopeproteingp120initsdimericformviahighmannose
oligosaccharides[119,121]. MMRplaysasubstantialroleinthebindingandtransmissionofHIV-1by
macrophagesasdemonstratedbyinhibitionwithmannan,mannose,ethylenediaminetetraaceticacid
(EDTA),andsolublemannose-bindinglectin[119,121]. Indeed,macrophageswereabletomediate
transmissionofboundHIVtoco-culturedTcells,andthistransmissioncouldbeblockedbyinhibitors
ofMMRbinding.
BesidesHIV-1,MMRalsorecognizesenvelopeglycoproteinsofothervirusesincludingtheDV
envelope(E)glycoprotein. ItwasshownthatMMRboundtomosquitoandhumancell-producedDV
antigenviaitsCRDswhichwasabrogatedbydeglycosylationoftheDVenvelopeglycoprotein[122].
DV infection of human macrophages was efficiently blocked by anti-MR antibodies indicating
afunctionalroleforMMRinDVinfection. Inaddition, MMRtogetherwiththeCLRmacrophage
galactose-type lectin (MGL; see below) contributes to endocytic uptake of influenza virus into
macrophages [123]. MMR bound to influenza virus via its CRDs in a Ca2+-dependent manner.
CompetitiveinhibitionofMMRusingmultivalentligandsledtoreducedinfluenzavirusinfection
of macrophages. Interestingly, influenza virus also bound to sialic acid residues present on
the MMR suggesting that MMR may act as a secondary receptor or co-receptor for infection of
macrophages[123,124]. AnothervirusrecognizedbyMMRisHBV.MMRwasshowntobeinvolved
in HBV surface antigen (HBsAg) recognition and uptake by DCs. Since HBsAg-positive DC were
frequentlyfoundintheliverofHBVpatients,MMR-mediatedinteractionbetweenHBsAgandDCs
mayoccurintheliverasthemainsiteofHBVinfection[125].
3.8. MacrophageGalactose-TypeLectin
TheCLRMacrophagegalactoseC-typelectin,MGL,isexpressedbymonocyte-derivedimmature
DCsandmacrophages. MGLisatypeIItransmembraneproteinwithaligandspecifityforgalactose