Human monocytes/macrophages are a target ofNeisseria meningitidis Adhesin A(NadA)

Abstract

Specific surface proteins of Neisseria meningitidis have been proposed to stimulate leukocytes during tissue invasion and septic shock. In this study, we demonstrate that the adhesin N. meningitidis Adhesin A (NadA) involved in the colonization of the respiratory epithelium by hypervirulent N. meningitidis B strains also binds to and activates human monocytes/macrophages. Expression of NadA on the surface on Escherichia coli does not increase bacterial-monocyte association, but a NadA-positive strain induced a significantly higher amount of TNF-alpha and IL-8 compared with the parental NadA-negative strain, suggesting that NadA has an intrinsic stimulatory action on these cells. Consistently, highly pure, soluble NadA(Delta351-405), a proposed component of an antimeningococcal vaccine, efficiently stimulates monocytes/macrophages to secrete a selected pattern of cytokines and chemotactic factors characterized by high levels of IL-8, IL-6, MCP-1, and MIP-1alpha and low levels of the main vasoactive mediators TNF-alpha and IL-1. NadA(Delta351-405) also inhibited monocyte apoptosis and determined its differentiation into a macrophage-like phenotype.

Neisseria meningitidis Adhesin NadA Targets β1 Integrins

“…By using soluble recombinant GFP-tagged CEACAMs and Y. enterocolitica expressing yadA or nadA and N. gonorrhoeae as controls we could demonstrate by flow cytometry that neither NadA nor YadA are recognized by CEACAM 1, 3, 5, 6, or 8, respectively. Previously it has been demonstrated that NadA induces chemokine IL-8 production of diverse host cell types similar to Yersinia Inv which is recognized by ␤1 integrins (14,(35)(36)(37). This prompted us to check whether NadA could also interact with ␤1 integrins.…”

“…Moreover, antigen-presenting dendritic cells (DCs), macrophages and neutrophils, which have been recruited to bacterial entry sides, also express ␣4␤1 and/or ␣5␤1 integrins. In analogy to invasin-expressing Yersinia it is not unlikely that N. meningitidis interacts through NadA with ␣␤1 integrins of M-cells of the NALT and with DCs, macrophages and neutrophils of the submucosa (14,24,36).…”

“…Whereas YadA of enteropathogenic Yersinia species mediates binding to diverse ECM proteins (9 -12), epithelial cells, and neutrophils, NadA of N. meningitidis does not bind to ECM proteins but binds to a restricted number of cell types such as Chang cells, HEp-2 or human monocytes/macrophages but fails to bind to HUVEC endothelial cells or human endometrium cell line Hec-1B (13)(14)(15).…”

Mapping of theNeisseria meningitidisNadA Cell-Binding Site: Relevance of Predicted α-Helices in the NH2-Terminal and Dimeric Coiled-Coil Regions

“…Indeed, NadA-specific receptors were observed also on monocytes, macrophages, and monocyte-derived dendritic cells (9,13). NadA may stimulate antimeningococcal defenses by augmenting the immune response of dendritic cells (self-adjuvant effect) and by increasing antigen presentation by macrophages engaged in antimicrobial activity (9,13,17).…”

“…In vitro observations indicated that NadA may also be important in mucosal colonization by N. meningitidis B: (i) its expression in Escherichia coli enhances bacterial association with Chang epithelial cells (a human conjunctiva cell line widely used in meningococcal pathogenesis studies) (2); (ii) a NadA knockout mutant of N. meningitidis shows a partial, yet significant, decrease in cell adhesion and invasion compared to a wild-type strain, suggesting that NadA cooperates with other factors in mediating bacterium-cell interactions (2); (iii) a soluble recombinant form of NadA (NadA with a deletion of residues 351 to 405 [NadA ⌬351-405 ]), lacking the membrane anchor region, binds to specific receptor sites with an apparent affinity of 3 M on Chang cells (2,9).…”