title: The streptococcal lipoprotein rotamase A (SlrA) is a functional peptidyl-prolyl isomerase involved in pneumococcal colonization.
abstract: 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 D39DeltaslrA 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.
authors.affiliation: Department of Pediatrics, University Medical Center St. Radboud, Nijmegen, The Netherlands.
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Hermans
authors.forename: Peter V
authors.initials: PV
authors.lastname: Adrian
authors.forename: Christa
authors.initials: C
authors.lastname: Albert
authors.forename: Silvia
authors.initials: S
authors.lastname: Estevão
authors.forename: Theo
authors.initials: T
authors.lastname: Hoogenboezem
authors.forename: Ingrid H T
authors.initials: IH
authors.lastname: Luijendijk
authors.forename: Thilo
authors.initials: T
authors.lastname: Kamphausen
authors.forename: Sven
authors.initials: S
authors.lastname: Hammerschmidt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D021984:Cyclophilin A / Q000737:chemistry; D021983:Cyclophilins / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D019696:Peptidylprolyl Isomerase / Q000737:chemistry* / Q000502:physiology; D010587:Phagocytosis; D011014:Pneumonia / Q000382:microbiology; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D013379:Substrate Specificity; D013997:Time Factors; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D008074:Lipoproteins; D010455:Peptides; D037521:Virulence Factors; D011392:Proline; D021984:Cyclophilin A; D021983:Cyclophilins; D019696:Peptidylprolyl Isomerase; C508148:SlrA protein, Streptococcus pneumoniae