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J. Biol. Chem., Vol. 281, Issue 2, 968-976, January 13, 2006

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The Streptococcal Lipoprotein Rotamase A (SlrA) Is a Functional Peptidyl-prolyl Isomerase Involved in Pneumococcal Colonization^*

Peter W. M. Hermans12, Peter V. Adrian13, Christa Albert¶, Silvia Estevão, Theo Hoogenboezem, Ingrid H. T. Luijendijk, Thilo Kamphausen||4, and Sven Hammerschmidt¶5

From the Department of Pediatrics, University Medical Center St. Radboud, 6500 HB Nijmegen, The Netherlands, the Department of Pediatrics, Erasmus Medical Center, Sophia Children's Hospital, 3000 DR Rotterdam, The Netherlands, the ^¶Research Center for Infectious Diseases, University of Würzburg, 97070 Würzburg, Germany, and the ^||Max-Planck-Research Unit for Enzymology of Protein Folding, 06120 Halle, Germany

Streptococcus pneumoniae expresses two surface-exposed lipoproteins, PpmA and SlrA, which share homology with distinct families of peptidyl-prolyl isomerases (PPIases). In this study, we demonstrated for the first time that the lipoprotein cyclophilin, SlrA, can catalyze the cis-trans isomerization of proline containing tetrapeptides and that SlrA contributes to pneumococcal colonization. The substrate specificity of SlrA is typical for prokaryotic and eukaryotic cyclophilins, with Suc-Ala-Ala-Pro-Phe-p-nitroanilide (pNA) being the most rapidly catalyzed substrate. In a mouse pneumonia model the slrA knock-out D39slrA did not cause significant differences in the survival times of mice compared with the isogenic wild-type strain. In contrast, a detailed analysis of bacterial outgrowth over time in the nasopharynx, airways, lungs, blood, and spleen showed a rapid elimination of slrA mutants from the upper airways but did not reveal significant differences in the lungs, blood, and spleen. These results suggested that SlrA is involved in colonization but does not contribute significantly to invasive pneumococcal disease. In cell culture infection experiments, the absence of SlrA impaired adherence to pneumococcal disease-specific epithelial and endothelial non-professional cell lines. Adherence of the slrA mutant could not be restored by exogenously added SlrA. Strikingly, deficiency in SlrA did not reduce binding activity to host target proteins, but resulted in enhanced uptake by professional phagocytes. In conclusion, SlrA is a functional, cyclophilin-type PPIase and contributes to pneumococcal virulence in the first stage of infection, namely, colonization of the upper airways, most likely by modulating the biological function of important virulence proteins.

Received for publication, September 12, 2005

^* This work was supported in part by Deutsche Forschungsgemeinschaft Sonderforschungsbereich 479, Teilprojekt A7 (to S. H.), the Bundesministerium für Bildung und Forschung CAPNETZ C8 (to S. H.), the Netherlands Foundation for Medical Research and Entrepreneurship STIGON project 014-81-114 (to S. E. and P. V. A.), and the Sophia Children's Hospital Foundation SSWO Project 297 (to P. V. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^{1 1} Both authors contributed equally to this work.

^{3 3} Present address: University of the Witwatersrand, Johannesburg, South Africa.

^{4 4} Present address: Strathmann Biotec AG, Bovenau, Germany.

² To whom correspondence may be addressed: Laboratory of Pediatric Infectious Diseases, University Medical Center St. Radboud, P. O. Box 9101 (internal post 184), 6500 HB Nijmegen, The Netherlands, Tel.: 31-24-3666406; Fax: 31-24-3616428; E-mail: p.hermans{at}cukz.umcn.nl. ⁵ To whom correspondence may be addressed: Röntgenring 11, Würzburg, D-97070, Germany. Tel.: 49-931-31-2153; Fax: 49-931-31-2578; E-mail: s.hammerschmidt{at}mail.uni-wuerzburg.de.

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