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Infect. Immun. doi:10.1128/IAI.00184-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The interaction of Streptococcus pneumoniae with plasmin mediates transmigration across endothelial and epithelial monolayers by intercellular junctions cleavage

Institut de Biologie Structurale Jean-Pierre Ebel UMR 5075, Laboratoire d'Ingénierie des Macromolécules, 41 rue Jules Horowitz, 38027 Grenoble, France; CEA; CNRS; Université Joseph Fourier, Partnership for Structural Biology

^* To whom correspondence should be addressed. Email: vernet{at}ibs.fr.

	Abstract

The precise mechanisms by which Streptococcus pneumoniae overcomes epithelial and endothelial barriers to access the underlying human tissues remain to be determined. The plasminogen system is highly important for tissues barriers degradation, which allows cell migration. The plasminogen is known to interact with the pneumococcus via the enolase, GAPDH and Choline-Binding Protein E. These observations prompted us to evaluate the role of this proteolytic system in pneumococcal invasion process. We observed that coating of S. pneumoniae R6 strain with plasminogen or inactivated plasmin increased adherence to pulmonary epithelial A549 and vascular endothelial EaHy cells in vitro. This indicates that plasminogen-mediated adherence is independent from the protease activity and involves plasminogen binding to receptors on eucaryotic cell surfaces. Inversely, decreased adherence of bacterial cells coated with active plasmin was observed, indicating that the protease activity limits bacterial attachment on cell surface. We were then interested in investigating the role of the proteolytic plasmin activity in the traversal of the tissues barriers. We observed that adherence of plasmin-coated D39 (encapsulated) or R6 (unencapsulated) pneumococci induced sporadic disruptions of EaHy and A549 monolayers cell junctions. This was not observed when plasmin was inhibited by aprotinin. Endothelial junctions disorganization may proceed by proteolysis of the cell junction components. This is supported by our observation of the in vitro cleavage by plasmin bound to pneumococci, of recombinant vascular endothelial cadherin, the main component of endothelial adherens junctions. Finally, junction damages induced by plasmin can be related to tissue barriers traversal as we measured an increase of the S. pneumoniae transmigration across epithelial A549 and endothelial EaHy layers when active plasmin was present on the bacterial surface. Our results highlight a novel function for the plasminogen recruitment at the bacterial surface in facilitating adherence of pneumococcus to endothelial and epithelial cells, while active plasmin degrades intercellular junctions. This process promotes migration of pneumococcus through cell barriers by a pericellular route, a pre-requisite for dissemination of S. pneumoniae in the host organism.