Co-ordinate action of bacterial adhesins and human carcinoembryonic antigen receptors in enhanced cellular invasion by capsulate serum resistant Neisseria meningitidis

Abstract

Neisseria meningitidis (Nm) is a human specific opportunistic pathogen that occasionally penetrates mucosal barriers via the action of adhesins and invasins and evades host immune mechanisms during further dissemination via capsule expression. From in vitro studies, the primary adhesion of capsulate bacteria is believed to be mediated by polymeric pili, followed by invasion via outer membrane adhesins such as Opa proteins. As the latter requires the surface capsule to be down-modulated, invading bacteria would be serum sensitive and thus avirulent. However, there is recent evidence that capsulate bacteria may interact via Opa proteins when host cells express high levels of carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), their target receptors. Such a situation may arise following increased circulation of inflammatory cytokines that upregulate certain adhesion molecules on host cells. In this study, using a tetracycline controlled expression system, we have developed cell lines with inducible CEACAM expression to mimic post-inflammation state of target tissues and analysed the interplay between the three surface components capsule, pili and Opa proteins in cellular interactions. With two distinct cell lines, not only the level but also the rate of adhesion of capsulate Opa-expressing Nm increased concurrently with CEACAM density. Moreover, when threshold levels of receptor were reached, cellular invasion ensued in an Opa-dependent manner. In studies with cell lines intrinsically expressing pilus receptors, notable synergism in cellular interactions between pili and Opa of several meningococcal strains was observed and was independent of capsule type. A number of internalized bacteria were shown to express capsule and when directly isolated from host cells, these bacteria were as serum resistant as the inoculated phenotype. Furthermore, we observed that agents that block Opa-CEACAM binding substantially reduced cellular invasion, while maintaining a low level of cellular adhesion. These studies highlight some of the factors that may determine increased host susceptibility to infection by serum resistant phenotypes; and demonstrate the potential of selective inhibition of key interactions in preventing target tissue penetration while maintaining a level of colonization.

Opa+and Opa−Isolates ofNeisseria meningitidisandNeisseria gonorrhoeaeInduce Sustained Proliferative Responses in Human CD4+T Cells

“…In accordance with our previous observations and those of others for a variety of cell types expressing CEACAM1 (with constitutive expression as well as transfected or stimulated to express the receptor) (2,3,32,40,44), N. meningitidis variants expressing Opa proteins adhered in significantly greater numbers to CEACAM1-expressing T cells than did Opa Ϫ variants. Prior to this study, no formal demonstration of Opa-expressing N. meningitidis adhesion to T cells had been performed.…”

Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models

“…Such an effect may involve localization of LR to lipid rafts (33), structures that have been implicated in invasion of host cells by a growing number of viral and bacterial pathogens (34). Our finding that upregulation of LR on the surface of eukaryotic cells is required for adherence is consistent with the need for increased expression of carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) to demonstrate binding by Opa proteins (32). Inflammation during the bacteremic phase of disease prior to onset of meningitis is likely to be important for upregulating LR prior to its interaction with bacteria.…”

“…The interaction with LR is likely to complement the numerous other ligand-receptor interactions used by these bacteria and may act synergistically with them to promote adherence and invasion (32). Such an effect may involve localization of LR to lipid rafts (33), structures that have been implicated in invasion of host cells by a growing number of viral and bacterial pathogens (34).…”

Two Strikingly Different Signaling Pathways Are Induced by Meningococcal Type IV Pili on Endothelial and Epithelial Cells

“…It has been shown that the Opa proteins may act in synergism with the type IV pilus-mediated adhesion to ensure bacterial invasion in epithelial cells (26). A large number of Opa receptors, i.e., the CEACAM family receptors, is critical for Opa-CEACAM interaction in a capsulated background.…”