Carcinoembryonic Antigen Family Receptor Specificity of Neisseria meningitidis Opa Variants Influences Adherence to and Invasion of Proinflammatory Cytokine-Activated Endothelial Cells

Abstract

The carcinoembryonic antigen (CEA) family member CEACAM1 (previously called biliary glycoprotein or CD66a) was previously shown to function as a receptor that can mediate the binding of Opa protein-expressing Neisseria meningitidis to both neutrophils and epithelial cells. Since neutrophils and polarized epithelia have both been shown to coexpress multiple CEACAM receptors, we have now extended this work to characterize the binding specificity of meningococcal Opa proteins with other CEA family members. To do so, we used recombinant Escherichia coli expressing nine different Opa variants from three meningococcal strains and stably transfected cell lines expressing single members of the CEACAM family. These infection studies demonstrated that seven of the nine Opa variants bound to at least one CEACAM receptor and that binding to each of these receptors is sufficient to trigger the Opa-dependent bacterial uptake by these cell lines. The other two Opa variants do not appear to bind to either CEACAM receptors or heparan sulfate proteoglycan receptors, which are bound by some gonococcal Opa variants, thus implying a novel class of Opa proteins. We have also extended previous studies by demonstrating induction of CEACAM1 expression after stimulation of human umbilical vein endothelial cells with the proinflammatory cytokine tumor necrosis factor alpha, which is present in high concentrations during meningococcal disease. This induced expression of CEACAM1 leads to an increased Opa-dependent bacterial binding and invasion into the primary endothelia, implying that these interactions may play an important role in the pathogenesis of invasive meningococcal disease.

CEACAM1 Dynamics during Neisseria gonorrhoeae Suppression of CD4+ T Lymphocyte Activation

“…At each time point, T cell association with Opa-deficient bacteria tended to be lower than with the other bacterial strains. Although other cell types that express CEACAM1, including epithelial (7, 17, 19 -22), endothelial (37), and professional phagocytic (21) cells, effectively engulf Opa CEA -expressing bacteria, we did not observe intracellular gonococci in the T cells. This implies that the inhibitory effect of gonococci (3) is mediated by signaling from CEACAM1 bound at the T cell surface.…”

“…However, our studies further indicate that the CEACAM1 must be bound by either CEACAM1-specific Abs or neisserial Opa CEA protein to retain CEACAM1 on the T cell surface. In fact, in contrast to all other cell types that express CEACAM1 (21,37,44), Opa CEA binding to T cells does not result in bacterial engulfment. Whether this results from different signaling and/or an absence of cellular machinery necessary to internalize bacteria in the T lymphocytes vs other cell types remains unknown.…”

Dual Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 in Angiogenesis and Invasion of Human Urinary Bladder Cancer

“…Similar to VEGF (3), VEGF-C and VEGF-D also may activate CEACAM1 expression in vascular endothelial cells, but this needs additional studies. It recently was shown that tumor necrosis factor ␣ is able to induce CEACAM1 expression in human endothelial cells (29). Whether additional tumor-secreted angiogenic factors and cytokines are involved in the induction of CEACAM1 expression in endothelial cells remains to be studied.…”

Profiling of bacterial adhesin — host receptor recognition by soluble immunoglobulin superfamily domains

“…These highly glycosylated proteins are anchored to the membrane either by glycosylphosphatidylinositol (GPI) moieties (CEA, CEACAM6, CEACAM7, CEACAM8) or by transmembrane and cytoplasmic domains (CEACAM1, CEACAM3, CEACAM4). Opa CEA -CEACAM interaction has been found for four members of the CEACAM-family, namely CEACAM1, CEACAM3, CEA and CEACAM6 (Bos et al, 1997;GrayOwen et al, 1997b;Muenzner et al, 2000). Depending on the CEACAM isoform involved, engagement of these receptors can result in different outcomes for the bacteria.…”