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2004-01-07

Phagocytosis, innate immunity, and host-pathogen specificity

Phillip Henneke

Et al.

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Repository Citation Henneke P, Golenbock DT. (2004). , innate immunity, and host-pathogen specificity. Open Access Articles. https://doi.org/10.1084/jem.20031256. Retrieved from https://escholarship.umassmed.edu/oapubs/1036

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The Journal of Experimental Medicine

Published January5,2004

ings aretheonlyreservoirfor email: [email protected] Freiburg, Germany.Phone:49-761-2704300; Fax:49-761-2704454; or PhillipHenneke,Children’s Hospital, Mathildenstr.1,79106 856-5980; Fax:(508)856-5463;email: [email protected]; School, 364PlantationSt.,LRB309, Worcester,MA01605.Phone:(508) Address correspondencetoDouglas T.Golenbock,UMASSMedical exclusively ongranulocytesandappearstofunctionspecif- CEACAM3 isasinglechainmoleculethatexpressed mental challenges. that hasevolvedtomatchdistinctspecies-specificenviron- shared bymanyspecies,andtheinterspeciesreceptordiversity nized bymoleculesoftheinnateimmunesystemthatare into howbroadclassesofmicrobialsubstructuresarerecog- are criticalforhostsurvival.Herewediscussnewinsights early eventsthataremediatedbytheinnateimmunesystem allowing theinductionofacquiredimmunity(1).These can bepresentedatthecellsurface(antigenpresentation), attack. Asaresultofthisprocess,pathogen-derivedmolecules sosome aredestroyedbyloweredpH,hydrolysis,andradical uration intoaphagolysosome.Pathogensinsidethephagoly- in phagosomeformation,whichprecedesmat- around theparticle.Fusionofmembraneextensionsresults followed bytheformationofactin-richmembraneextensions binding andrecognitionofparticlesbycellsurfacereceptors, Phagocytosis comprisesaseriesofevents,startingwiththe invading pathogens,whichisthefocusofthiscommentary. an earlyandcrucialeventintriggeringhostdefensesagainst clearance ofdyingcells.Furthermore,phagocytosisrepresents logical events,includingtissueremodelingandthecontinuous duction pathwaythatinvolvesthesmallGTPase,Rac. mediates bacterialinternalization(3,4)viaasignaltrans- scrutiny, notonlybindstheseuniquelyhumanbacteriabut family ofreceptors,whichisnowthesubjectintense known asCD66d).CEACAM3,amemberoftheCD66 antigen–related celladhesionmolecule3(CEACAM3,also via auniquesurfacereceptorknownascarcinoembryonic highly adaptedspeciesofcommensalGram-negativebacteria by whichthehumanimmunesystemrecognizesthese thisissue,Schmitteretal.(2)describetheelegantmanner In gonorrhoeae

CEACAM3: APhagocyticReceptorinMan. In mammals,phagocytosisisessentialforavarietyofbio-

,

Haemophilus influenza

1 Phagocytosis, InnateImmunity, andHost–Pathogen Specificity 2 1 Phillip Henneke Commentary University of Massachusetts MedicalSchool,University ofMassachusetts DivisionofInfectiousDiseasesandImmunology, Worcester, MA01605 Children’s Hospital, Albert-Ludwigs-University, 79106Freiburg, Germany Neisseria meningitidis , http://www.jem.org/cgi/doi/10.1084/jem.20031256 1–4 January5,2004 Volume 199,Number 1, J. Exp.Med.

and Moraxella catarrhalis  Human be- 1 TheRockefeller UniversityPress andDouglas T. Golenbock and N. . mucosal surfacesofhumans. The immediateandnonphlo- H. influenza to beafrequentevent,particularly forthespeciesof mediating LPSresponses(6). even thoughsomeCRsmayhavecoreceptorcapabilities in CR-mediated phagocytosisitselfisnoninflammatory(1,5), FcR mediatedphagocytosisisstronglyproinflammatory, uptake revealsremarkabledifferencesinoutcome:whereas even thecomparisonofFcR-andCR-mediatedparticle of both theinvadingorganismandhost.Surprisingly, fate to elicitaspecificresponseparticlesthatdeterminesthe during thephagocyticprocess.Thisenablesphagocyte phagocyte interactioncanconcurrentlysampletheparticle surface receptorspresentatthetimeofinitialparticle– and complementreceptors(CRs).Asoutlinedbelow, other to recognizetheparticleindirectlyviaFcreceptors(FcRs) process knownasopsonization.Thisallowsthephagocyte ponents suchasantibodiesorcomplementcomponents,a First, theinfectiousparticlesbecomeboundbyserumcom- microbes byphagocytesistypicallycomparativelynonspecific. of CEACAM3withcommensals,theinitialuptakemost achieved? Incontrasttothehighlyspecies-specificinteractions nity. mind arelatedbroaderquestionaboutinnateimmu- The findingsonCEACAM3and interact withthesamereceptor. how theseproteins,whichdonotshareoverthomology, the humanimmuneresponse.Whatremainsunansweredis over time,amechanismthatmighthelppathogensto OPA ,P5andUspA1,undergomolecularvariation M. catarrhalis bacterial surfaceproteinsP5of suggest CEACAM3tobeaphagocyticreceptorforthe opacity (OPA)proteinfamily.Accordingly,Schmitteretal. gonorrhoeae gonorrhoeae nonhuman primates,matchingthespecies-specificityof organisms, CEACAM3hasnohomologueinrodentsand which hasancientorthologsinfliesandotherprimitive Unlike theTollreceptorfamilyofinnateimmunereceptors, associated signaltransductioneventsdrivenbythesebacteria. ically inthephagocytosisofcommensalbacteriaand General ParadigmsinthePhagocytosisofMicrobialPathogens. The invasionofsmallnumbers ofbacteriacanbeassumed How isthespecificityofhost–pathogeninteraction , CEACAM3interactswiththe11-membered , H. influenza , and (2),whichareknowntobindCEACAMs. •0022-1007/2004/01/1/4 $8.00 2 M. catarrhalis , and M. catarrhalis thatcommonlycolonizethe H. influenzae Neisseria spp. . Inthecaseof andUspA1of bringto Neisseria evade N. N.

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on July 15, 2008 2008 15, July on www.jem.org from Downloaded

Published January 5, 2004

gistic removal of bacteria from the blood and tissue pre- ila melanogaster express a transmembrane cell surface re- vents the host from succumbing to bacterial spread, septic ceptor designated peptidoglycan recognition LC mestastasis, and subsequent generalized inflammation and is (PGRP-LC), which specifically recognizes Gram-nega- a critically important feature of the innate immune system. tive bacteria. Recognition of Gram-negative bacteria by Phagocytic leukocytes, including both tissue macrophages PGRP-LC activates a signaling pathway, which drives the and granulocytes, play a crucial role in this process. Corre- expression of antibacterial peptide (13). The study of sponding to the importance of early recognition of bacteria the 13 PGRPs in flies and their mammalian orthologs has and the delivery of a cellular response, numerous proteins led to some major surprises. For example, the discovery of assemble at the point where the phagocyte membrane and TLR4 as the LPS receptor was directly due to work that the invading microbe meet. Extensive horizontal commu- others had done in Drosophila. Subsequently, other human nication among the membrane proteins that multimerize at TLRs were identified as peptidoglycan recognition pro- the developing phagosome and the delivery of multiple, teins. Incredibly, fly Toll receptors (of which there are overlapping and synergistic signals across the membrane are nine) apparently play no role in LPS or peptidoglycan rec- the consequences. ognition (14). Although four PGRP homologues exist in Evolutionary Conserved Particle Recognition and Initiation of humans, they do not appear to be expressed as receptors Inflammation. In contrast to the CEACAMs, phagocyte by human macrophages (15). One mammalian PGRP, receptors that trigger the transcription of inflammatory PGRP-L, is an enzyme that digests peptidoglycan, an genes upon internalization of a microbe are remarkably N-acetylmuramyl-l-alanine amidase. In fact, all PGRP pro- conserved through evolution. The most important recep- teins are structurally related to this family of enzymes, but tors for the initiation of inflammatory signals are the Toll- only a subset are likely to be enzymatic. Mouse PGRP-S is like receptors (TLRs) and proteins containing a nucleotide- not enzymatic but is somehow required for efficient neu- binding oligomerization domain (NOD). The deficiency of trophil-based killing of nonpathogenic Gram-positive bac- Downloaded from specific TLRs and various adaptor proteins of the TLR sig- teria (16). The function of the two other mammalian nal transduction pathway, such as MyD88 and IL-1 recep- PGRPs is unknown. PGRP-L may orchestrate highly spe- tor–associated kinase 4, have been shown to result in re- cific cellular responses to Gram-negative bacteria such as duced bacterial clearance and a poor host responses to Neisseria, but its role in immunity is still largely unknown.

microorganisms, both in human beings and experimentally For all of our reliance on lower species of animals to inform www.jem.org infected rodents (7, 8). The interaction between microbial us about the shape of the mammalian innate immune sys- particles and TLR pathways in granulocytes alone is highly tem, we are gradually coming back to the obvious conclu- complex, as exemplified for Neisseria spp. Among the mul- sion that man is not a fly.

tiple known molecular substructures of Neisseria that serve Rho Down the Stream. The interface between microbial on July 15, 2008 as ligands for phagocyte receptors, the lipopolysaccharide particles and the phagocyte is critical for the specificity of from Neisseria interacts exclusively with TLR4. TLR2, to- the host response. Receptor–ligand interactions are at the gether with TLR1 and TLR6, recognize at least three cell heart of understanding how the innate immune system de- wall components of Neisseria: peptidoglycan fragments, stroys microbes. However, downstream events are also im- porins, and the Lip lipoprotein (9, 10). It has been reported portant to both transcriptional activation of inflammatory that subtle changes in the degree of acylation of bacterial li- genes and activity of the actin skeleton. In the case of poproteins determines whether TLR1 or TLR6 serves as a TLRs, four intracellular proteins (MyD88, TRIF, MAL/ coreceptor for TLR2, exemplifying the finely tuned nature TIRAP, TIRP/TRAM) are known to function as adaptors of TLR recognition (11). Peptidoglycan fragments from N. that connect the activation of TLRs to the transcription ap- meningitidis are also recognized by an intracellular receptor, paratus (17). In addition to these adapters, phosphatidyli- NOD2, which drives transcriptional activation via NF-B nositol-3 kinase (PI-3K) has been found to associate with (12). Peptidoglycan fragments (MurNAc-L-Ala-D-IsoGln) TLR2, a receptor for cell wall material of bacteria and par- from Gram-positive and -negative bacteria are detected by asites, via two putative binding domains (YxxM, YxxW) the intracellular receptor NOD2, whereas other pepti- for the p85 subunit of PI-3K in the cytoplasmic domain of doglycan fragments (GlcNAc-MurNAc-l-Ala--D-Glu-meso- TLR2 (tyrosine residues 616 and 761). In turn, Rac1, a DAP) specific for Gram-negative bacteria are detected by member of the Rho family of proteins, binds to PI-3K. NOD1 (12). Thus NOD1 and NOD2 are striking exam- The interaction between TLR2 and Rac1 appears to be ples of sophisticated solutions that allow the discrimination important for transcriptional activation (NF-B) in re- between different pathogens that manage to invade the in- sponse to cell wall preparations from S. aureus (18). Inter- tracellular space of cells. estingly, CEACAM3 contains similar YxxM motifs in the Peptidoglycan Recognition Protein LC: A Phagocytic Receptor ITAM-like sequence of its cytoplasmic tail and colocalizes in Flies. As the role of the CEACAM, TLR, and NOD with Rac. Hence, it appears that Neisseria activate Rho proteins becomes increasingly well delineated, alternative proteins in a dual fashion via both TLR2 and CEACAM3. means of bacterial recognition are being identified also. As Mounting evidence indicates that the Rho family of with the TLRs, an evolutionary perspective has helped us small GTPases, which consists of at least 16 mammalian understand the potential role of these new proteins in host members, mediates fine particle recognition by phagocytes. responses to bacteria. Immune-responsive cells in Drosoph- Rho proteins are often described as molecular switches be-

2 Commentary

Published January 5, 2004

cause they cycle between an active (GTP-bound) to an in- mune recognition can be established to better understand active (GDP-bound) conformation similar to many hun- the pathogenesis of infectious diseases in man. dred other GTPase switches in mammalian cells. The careful regulation of the GTPase activity is assured by over This work was supported in part by the Deutsche Forschungsge- 60 activators and a similar number of inactivators (19). In meinschaft (He 3127/2-1 to P. Henneke) and the National Institutes addition, Rho proteins couple changes of the environment of Health (ROI AI52455 and ROI GM54060 to D.T. Golenbock). to intracellular signal transduction events. Greater than 60 Submitted: 3 December 2003 targets of Rho activity have been identified to date (20). Accepted: 10 December 2003 First, most Rho proteins affect the organization of poly- merized actin (F-actin). RhoA, for example, induces acto- myosin-based contractility leading to the formation of stress References fibers. Rac and Cdc42 stimulate the formation of mem- 1. Aderem, A. 2003. Phagocytosis and the inflammatory re- brane extensions designated lamellipodia (Rac) and the sponse. J. Infect. Dis. 187:S340–S345. more finger-like filopodia (Cdc42) (21). Furthermore, 2. Schmitter, T., F. Agerer, L. Peterson, P. Munzer, C.R. Cdc42 is essential for daughter cell growth of budding Hauck. 2004. Granulocyte CEACAM3 is a phagocytic re- yeast. Rho proteins drive actin-based vesicle transport ceptor of the innate immune system that mediates recogni- around the cell (22) and are involved in cell contraction tion and elimination of human-specific pathogens. J. Exp. and membrane blebbing, which are hallmarks of apoptotic Med. 199:35–46. cell morphology (23). Whereas effects on actin polymeriza- 3. Chen, T., and E.C. Gotschlich. 1996. CGM1a antigen of tion are probably the best studied functions of the Rho neutrophils, a receptor of gonococcal opacity proteins. Proc. families, many other features of these proteins such as mi- Natl. Acad. Sci. USA. 93:14851–14856. 4. Hauck, C.R., T.F. Meyer, F. Lang, and E. Gulbins. 1998. Downloaded from crotubule dynamics, adhesion, cell cycle progression, and CD66-mediated phagocytosis of Opa52 Neisseria gonorrhoeae control of transcription have been revealed. requires a Src-like tyrosine kinase- and Rac1-dependent sig- It is exciting to ponder the observation that bacteria nalling pathway. EMBO J. 17:443–454. have evolved toxins that target the Rho family in order to 5. Henneke, P., O. Takeuchi, R. Malley, E. Lien, R.R. Ingalls, escape the immune response. Clostridium species and M.W. Freeman, T. Mayadas, V. Nizet, S. Akira, D.L.

Staphylococcus aureus secrete toxins that inactivate Rho pro- Kasper, and D.T. Golenbock. 2002. Cellular activation, www.jem.org teins via ADP-ribosylation or glucosylation (24), whereas phagocytosis, and bactericidal activity against group B strep- Pseudomonas aeruginosa and Yersinia spp. inject proteins sim- tococcus involve parallel myeloid differentiation factor 88- ilar to the GTPase-activating protein into eukaryotic cells dependent and independent signaling pathways. J. Immunol. 169:3970–3977.

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4 Commentary