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Infection and Immunity, August 2007, p. 4116-4126, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.01835-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Opa Proteins of Pathogenic Neisseriae Initiate Src Kinase-Dependent or Lipid Raft-Mediated Uptake via Distinct Human Carcinoembryonic Antigen-Related Cell Adhesion Molecule Isoforms ^,

Tim Schmitter,^1,#, Stefan Pils,^2, Stephanie Weibel,¹ Franziska Agerer,^1, Lisa Peterson,¹ Alexander Buntru,² Kathrin Kopp,² and Christof R. Hauck^1,2*

Zentrum für Infektionsforschung, Universität Würzburg, Röntgenring 11, 97070 Würzburg, Germany,¹ Lehrstuhl für Zellbiologie, Universität Konstanz, Postfach X908, 78457 Konstanz, Germany²

Received 20 November 2006/ Returned for modification 24 January 2007/ Accepted 10 May 2007

Several pathogenic bacteria exploit human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) for adhesion to and invasion into their host cells. CEACAM isoforms have characteristic expression patterns on epithelial, endothelial, or hematopoietic cells, providing bacteria with distinct sets of receptors on particular tissues. For example, while CEACAM1 and CEACAM6 have a wide tissue distribution, CEACAM3, CEACAM4, and CEACAM8 are uniquely expressed on primary human granulocytes, whereas CEA and CEACAM7 are limited to epithelia. By reconstitution of a CEACAM-deficient cell line with individual CEACAMs, we have analyzed the requirements for CEACAM-mediated internalization of Neisseria gonorrhoeae. Our results point to two mechanistically different uptake pathways triggered by either epithelial CEACAMs (CEACAM1, CEA, and CEACAM6) or the granulocyte-specific CEACAM3. In particular, CEACAM3-mediated uptake critically depends on Src family protein tyrosine kinase (PTK) activity, and CEACAM3 associates with the SH2 domains of several Src PTKs. In contrast, epithelial CEACAMs require the integrity of cholesterol-rich membrane microdomains and are affected by cholesterol depletion, whereas CEACAM3-mediated uptake by transfected cells or the opsonin-independent phagocytosis by human granulocytes is not altered in the presence of cholesterol chelators. These results allow the subdivision of all human CEACAMs known to be utilized as pathogen receptors into functional groups and point to important consequences for bacterial engagement of distinct CEACAM isoforms.

Published ahead of print on 21 May 2007.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: J. N. Weiser

^# Present address: ACE BioSciences, 5220 Odense, Denmark.

These authors contributed equally.

Present address: Institut Caesar, 53175 Bonn, Germany.

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