CD66 carcinoembryonic antigens mediate interactions between Opa-expressing Neisseria gonorrhoeae and human polymorphonuclear phagocytes

Gray-Owen, Scott D.

doi:10.1093/emboj/16.12.3435

Cited by 202 publications

(253 citation statements)

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“…Opa 50 -expressing gonococci showed preference for Lec11 CEACAM1 cells and none of the other cell lines. Although Opa 50 interacts specifically with HSPG receptors (18,60), it does display a low level of CEACAM1 binding (20). Since Opa 50 binds the carbohydrate component of HSPGs, the difference in binding could plausibly be attributed to distinct CEACAM1 glycosylation patterns between the Lec11 cell lines and those previously used; however, detailed analysis of CEACAM glycosylation in these cells versus other cells has not been performed.…”

Section: Resultsmentioning

confidence: 98%

“…Postinfection, samples were washed with Hanks balanced salt solution (HBSS) and fixed using 3.7% paraformaldehyde. The cells were stained for CEACAM and bacteria and observed as described previously (18). Intracellular bacteria were differentiated from extracellular bacteria via exclusion of N. gonorrhoeae-specific antibody, as described previously (41).…”

Section: Discussionmentioning

confidence: 99%

“…N. gonorrhoeae isolates from both naturally infected men and women are predominantly Opa ϩ , as are isolates obtained from men experimentally infected with transparent (Opa phase-varied off) colonies (12)(13)(14). Most gonococcal Opa variants bind to one or more members of the human CEACAM family of receptors (15)(16)(17)(18)(19)(20). CEACAM receptors are members of the immunoglobulin (Ig) superfamily, containing an Ig variable-region-like N-terminal domain followed by a varying number of Ig constant-region-like domains exposed at the cell surface (21,22).…”

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confidence: 99%

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Selection for a CEACAM Receptor-Specific Binding Phenotype during Neisseria gonorrhoeae Infection of the Human Genital Tract

et al. 2015

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Infections by Neisseria gonorrhoeae are increasingly common, are often caused by antibiotic-resistant strains, and can result in serious and lasting sequelae, prompting the reemergence of gonococcal disease as a leading global health concern. N. gonorrhoeae is a human-restricted pathogen that primarily colonizes urogenital mucosal surfaces. Disease progression varies greatly between the sexes: men usually present with symptomatic infection characterized by a painful purulent urethral discharge, while in women, the infection is often asymptomatic, with the most severe pathology occurring when the bacteria ascend from the lower genital tract into the uterus and fallopian tubes. Classical clinical studies demonstrated that clinically infectious strains uniformly express Opa adhesins; however, their specificities were unknown at the time. While in vitro studies have since identified CEACAM proteins as the primary target of Opa proteins, the gonococcal specificity for this human family of receptors has not been addressed in the context of natural infection. In this study, we characterize a collection of low-passage-number clinicalspecimen-derived N. gonorrhoeae isolates for Opa expression and assess their CEACAM-binding profiles. We report marked in vivo selection for expression of phase-variable Opa proteins that bind CEACAM1 and CEACAM5 but selection against expression of Opa variants that bind to the neutrophil-restricted decoy receptor CEACAM3. This is the first study showing phenotypic selection for distinct CEACAM-binding phenotypes in vivo, and it supports the opposing functions of CEACAMs that facilitate infection versus driving inflammation within the genital tract.

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Selection for a CEACAM Receptor-Specific Binding Phenotype during Neisseria gonorrhoeae Infection of the Human Genital Tract

et al. 2015

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“…Stably transfected HeLa cell lines expressing the CEACAM1 (CD66a; BGP), CEACAM3 (CD66d; CGM1), CEACAM5 (CD66e; CEA), CEACAM6 (CD66c; NCA) and CEACAM8 (CD66b; CGM6) receptors (Berling et al, 1990;Nagel et al, 1993;Gray-Owen et al, 1997a) as well as the stably transfected CHO-CEACAM4 (CGM7) and CHO-CEACAM1 Oikawa et al, 1991) have been described previously. The CHO-CEA-CAM7 (CGM2) cell line (Schoelzel, S et al, data to be published) was a kind gift from Dr J. Thompson (Institut fu È r Immunbiologie, University of Freiburg, Germany).…”

Section: Cell Linesmentioning

confidence: 99%

“…Infection of transiently transfected cells was performed as for the stable cell lines, except that cells were initially seeded onto 12 mm glass coverslips and ®xed after the ®nal washing step of the infection experiment by incubation in 3.7% paraformaldehyde in 200 mM HEPES buffer (pH 7.4) for 30 min. Fixed samples were then immunocytochemically stained, and binding interactions were analysed by confocal laser scanning microscopy as described previously (Gray-Owen et al, 1997a).…”

Section: Bacterial Infection Assaysmentioning

confidence: 99%

Molecular analysis of neisserial Opa protein interactions with the CEA family of receptors: identification of determinants contributing to the differential specificities of binding

et al. 1999

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SummaryThe carcinoembryonic antigen (CEA) gene family members, CEACAM1, CEACAM3, CEACAM5 and CEA-CAM6, are bound by the Opa outer membrane proteins of pathogenic Neisseria spp., whereas CEACAM8 is not. In this study, we demonstrate that the closely related CEACAM4 and CEACAM7, which are also members of the CEA family, are not Opa receptors. We exploited the high conservation between CEACAM6 and CEACAM8 to generate an extensive set of chimeric receptors in order to delineate the sequences necessary for Opa binding. Using a transfection-based infection system, we showed that binding of Opa 52 involves residues 27±42, which are predicted to form b-strand C and short loops adjacent to it, and residues lying between amino acids 60 and 108 in the amino-terminal domain. The replacement of residues 27±29 in CEACAM6 with the CEACAM1 or CEACAM5 sequences generated recombinant CEA-CAM6 receptors that are bound by CEACAM1/CEA-CAM5-speci®c Opa variants. Together, our data demonstrate that Opa proteins bind to residues exposed on the GFCC 8 face of the N-terminal domain of CEACAM receptors, and identify an amino acid triplet sequence that is responsible for the differential binding of Opa proteins to CEACAM1, CEACAM5 and CEACAM6.

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Two new synthetic peptides from the N‐domain of CEACAM1 (CD66a) stimulate neutrophil adhesion to endothelial cells

Skubitz

2011

Biopolymers

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Four members of the carcinoembryonic antigen family, CEACAMs 1, 3, 6, and 8, are expressed on human neutrophils and can trigger an activation signal that increases neutrophil adhesion to human umbilical vein endothelial cell (HUVEC) monolayers. To identify active sites on CEACAM1, we previously performed molecular modeling using IgG and CD4 as models, and 28 peptides of 14 amino acids in length were synthesized that were predicted to be present at loops and turns between β-sheets. Three peptides, each from the N-terminal domain, increased neutrophil adhesion to HUVEC monolayers and upregulated cell-surface CD11b/CD18 expression on neutrophils. In our earlier study, one N-domain peptide (CD66a-7) was not successfully synthesized, and another N-domain peptide (CD66a-6) was not soluble in the assay system. In the present study, we have now successfully synthesized CD66a-7, and a new peptide (CD66a-6L), that is a modification of the peptide that was insoluble in the earlier study. Both of these new peptides increased neutrophil adhesion to HUVEC monolayers. Importantly, the amino acid sequence of CD66a-7 is identical to the homologous peptides from CEACAMs 3, 5, and 6, but differs from the homologous peptide of CEACAM8, which was not active in this system. CD66a-6L is identical to the homologous peptide from CEACAM6. The data suggest that peptide motifs from at least five regions of the N-terminal domain of CEACAM1 are involved in the interaction of CEACAM1 with other ligands and can initiate signal transduction in neutrophils. Some of these active peptides are identical to homologous regions of other CEACAMs.

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CD66 carcinoembryonic antigens mediate interactions between Opa-expressing Neisseria gonorrhoeae and human polymorphonuclear phagocytes

Cited by 202 publications

References 51 publications

Selection for a CEACAM Receptor-Specific Binding Phenotype during Neisseria gonorrhoeae Infection of the Human Genital Tract

Selection for a CEACAM Receptor-Specific Binding Phenotype during Neisseria gonorrhoeae Infection of the Human Genital Tract

Molecular analysis of neisserial Opa protein interactions with the CEA family of receptors: identification of determinants contributing to the differential specificities of binding

Two new synthetic peptides from the N‐domain of CEACAM1 (CD66a) stimulate neutrophil adhesion to endothelial cells

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