Published online before print April 28, 2009

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(Journal of Leukocyte Biology. 2009;86:143-153.)
© 2009 Society for Leukocyte Biology

The membrane expression of Neisseria meningitidis adhesin A (NadA) increases the proimmune effects of MenB OMVs on human macrophages, compared with NadA^– OMVs, without further stimulating their proinflammatory activity on circulating monocytes

Regina Tavano^*,1, Susanna Franzoso^*,1, Paola Cecchini^*, Elena Cartocci, Francesca Oriente, Beatrice Aricò and Emanuele Papini^*,2

^* CRIBI and Department of Biomedical Sciences, University of Padova, Italy; and
Novartis Vaccine and Diagnostics srl, Siena, Italy

2. Correspondence: C.R.I.B.I.-University of Padova, Via G. Colombo 3, 35121 Padova, Italy. E-mail: emanuele.papini{at}unipd.it

ABSTRACT

Hypervirulent MenB causing fatal human infections frequently display the oligomeric-coiled coil adhesin NadA, a 45-kDa intrinsic outer membrane protein implicated in binding to and invasion of respiratory epithelial cells. A recombinant soluble mutant lacking the 10-kDa COOH terminal membrane domain (NadA_351–405) also activates human monocytes/macrophages/DCs. As NadA is physiologically released during sepsis as part of OMVs, in this study, we tested the hypothesis that NadA⁺ OMVs have an enhanced or modified proinflammatory/proimmune action compared with NadA^– OMVs. To do this we investigated the activity of purified free NadA_351–405 and of OMVs from MenB and Escherichia coli strains, expressing or not full-length NadA. NadA_351–405 stimulated monocytes and macrophages to secrete cytokines (IL-1β, TNF-, IL-6, IL-12p40, IL-12p70, IL-10) and chemokines (IL-8, MIP-1, MCP-1, RANTES), and full-length NadA improved MenB OMV activity, preferentially on macrophages, and only increased cytokine release. NadA_351–405 induced the lymphocyte costimulant CD80 in monocytes and macrophages, and NadA⁺ OMVs induced a wider set of molecules supporting antigen presentation (CD80, CD86, HLA-DR, and ICAM-1) more efficiently than NadA^– OMVs only in macrophages. Moreover, membrane NadA effects, unlike NadA_351–405 ones, were much less IFN--sensitive. The activity of NadA-positive E. coli OMVs was similar to that of control OMVs. NadA in MenB OMVs acted at adhesin concentrations 10⁶ times lower than those required to stimulate cells with free NadA_351–405.

Key Words: chemokines • cytokines • cell activation • inflammation

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