title: The νSaα Specific Lipoprotein Like Cluster (lpl) of S. aureus USA300 Contributes to Immune Stimulation and Invasion in Human Cells.
abstract: All Staphylococcus aureus genomes contain a genomic island, which is termed νSaα and characterized by two clusters of tandem repeat sequences, i.e. the exotoxin (set) and 'lipoprotein-like' genes (lpl). Based on their structural similarities the νSaα islands have been classified as type I to IV. The genomes of highly pathogenic and particularly epidemic S. aureus strains (USA300, N315, Mu50, NCTC8325, Newman, COL, JH1 or JH9) belonging to the clonal complexes CC5 and CC8 bear a type I νSaα island. Since the contribution of the lpl gene cluster encoded in the νSaα island to virulence is unclear to date, we deleted the entire lpl gene cluster in S. aureus USA300. The results showed that the mutant was deficient in the stimulation of pro-inflammatory cytokines in human monocytes, macrophages and keratinocytes. Purified lipoprotein Lpl1 was further shown to elicit a TLR2-dependent response. Furthermore, heterologous expression of the USA300 lpl cluster in other S. aureus strains enhanced their immune stimulatory activity. Most importantly, the lpl cluster contributed to invasion of S. aureus into human keratinocytes and mouse skin and the non-invasive S. carnosus expressing the lpl gene cluster became invasive. Additionally, in a murine kidney abscess model the bacterial burden in the kidneys was higher in wild type than in mutant mice. In this infection model the lpl cluster, thus, contributes to virulence. The present report is one of the first studies addressing the role of the νSaα encoded lpl gene cluster in staphylococcal virulence. The finding that the lpl gene cluster contributes to internalization into non-professional antigen presenting cells such as keratinocytes highlights the lpl as a new cell surface component that triggers host cell invasion by S. aureus. Increased invasion in murine skin and an increased bacterial burden in a murine kidney abscess model suggest that the lpl gene cluster serves as an important virulence factor.
authors.affiliation: Department of Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Minh Thu
authors.initials: MT
authors.lastname: Nguyen
authors.affiliation: Department of Dermatology, University of Tübingen, Tübingen, Germany.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Kraft
authors.affiliation: Department of Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Yu
authors.forename: Dogan Doruk
authors.initials: DD
authors.lastname: Demircioglu
authors.affiliation: Department of Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Dogan Doruk
authors.initials: DD
authors.lastname: Demicrioglu
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hertlein
authors.affiliation: Department of Dermatology, University of Tübingen, Tübingen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Burian
authors.affiliation: Immunoregulation, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Mathias
authors.initials: M
authors.lastname: Schmaler
authors.affiliation: Paul-Ehrlich-Institut, Federal regulatory agency for Vaccines and Biomedicines, Langen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Boller
authors.affiliation: Paul-Ehrlich-Institut, Federal regulatory agency for Vaccines and Biomedicines, Langen, Germany; Institute of Medical Microbiology, Immunology, and Parasitology, University Hospital Bonn, Bonn, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bekeredjian-Ding
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Ohlsen
authors.affiliation: Department of Dermatology, University of Tübingen, Tübingen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schittek
authors.affiliation: Department of Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Götz
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004269:DNA, Bacterial / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D055786:Gene Knockout Techniques; D044404:Genomic Islands / Q000235:genetics*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D013203:Staphylococcal Infections / Q000235:genetics*; D013211:Staphylococcus aureus / Q000235:genetics* / Q000472:pathogenicity*; D014774:Virulence / Q000235:genetics*; D037521:Virulence Factors / Q000235:genetics
chemical_list: D004269:DNA, Bacterial; D037521:Virulence Factors