title: α-Hemolysin enhances Staphylococcus aureus internalization and survival within mast cells by modulating the expression of β1 integrin.
abstract: Mast cells (MCs) are important sentinels of the host defence against invading pathogens. We previously reported that Staphylococcus aureus evaded the extracellular antimicrobial activities of MCs by promoting its internalization within these cells via β1 integrins. Here, we investigated the molecular mechanisms governing this process. We found that S. aureus responded to the antimicrobial mediators released by MCs by up-regulating the expression of α-hemolysin (Hla), fibronectin-binding protein A and several regulatory systems. We also found that S. aureus induced the up-regulation of β1 integrin expression on MCs and that this effect was mediated by Hla-ADAM10 (a disintegrin and metalloproteinase 10) interaction. Thus, deletion of Hla or inhibition of Hla-ADAM10 interaction significantly impaired S. aureus internalization within MCs. Furthermore, purified Hla but not the inactive HlaH35L induced up-regulation of β1 integrin expression in MCs in a dose-dependent manner. Our data support a model in which S. aureus counter-reacts the extracellular microbicidal mechanisms of MCs by increasing expression of fibronectin-binding proteins and by inducing Hla-ADAM10-mediated up-regulation of β1 integrin in MCs. The up-regulation of bacterial fibronectin-binding proteins, concomitantly with the increased expression of its receptor β1 integrin on the MCs, resulted in enhanced S. aureus internalization through the binding of fibronectin-binding proteins to integrin β1 via fibronectin.
authors.affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Goldmann
authors.affiliation: Institute of Medical Microbiology, University Hospital of Jena, Erlanger Allee 101, 07747, Jena, Germany.
authors.forename: Lorena
authors.initials: L
authors.lastname: Tuchscherr
authors.affiliation: Central Facility for Microscopy, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Rohde
authors.affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Medina
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism; D018829:Adhesins, Bacterial / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D006460:Hemolysin Proteins / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D019012:Integrin beta1 / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism / Q000382:microbiology*; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D013207:Staphylococcal Skin Infections / Q000378:metabolism / Q000382:microbiology; D013211:Staphylococcus aureus / Q000472:pathogenicity* / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D018829:Adhesins, Bacterial; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D019012:Integrin beta1; D008565:Membrane Proteins; C078635:fibronectin-binding proteins, bacterial; C021091:staphylococcal alpha-toxin; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse