title: The Janus face of α-toxin: a potent mediator of cytoprotection in staphylococci-infected macrophages.
abstract: After phagocytosis by macrophages, Staphylococcus aureus evades killing in an α-toxin-dependent manner, and then prevents apoptosis of infected cells by upregulating expression of antiapoptotic genes like MCL-1 (myeloid cell leukemia-1). Here, using purified α-toxin and a set of hla-deficient strains, we show that α-toxin is critical for the induction of MCL-1 expression and the cytoprotection of infected macrophages. Extracellular or intracellular treatment of macrophages with α-toxin alone did not induce cytoprotection conferred by increased Mcl-1, suggesting that the process is dependent on the production of α-toxin by intracellular bacteria. The increased expression of MCL-1 in infected cells was associated with enhanced NFκB activation, and subsequent IL-6 secretion. This effect was only partially inhibited by blocking TLR2, which suggests the participation of intracellular receptors in the specific recognition of S. aureus strains secreting α-toxin. Thus, S. aureus recognition by intracellular receptors and/or activation of downstream pathways leading to Mcl-1 expression is facilitated by α-toxin released by intracellular bacteria which permeabilize phagosomes, ensuring pathogen access to the cytoplasmatic compartment. Given that the intracellular survival of S. aureus depends on α-toxin, we propose a novel role for this agent in the protection of the intracellular niche, and further dissemination of staphylococci by infected macrophages.
authors.affiliation: Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Koziel
authors.forename: Daniela
authors.initials: D
authors.lastname: Chmiest
authors.forename: Danuta
authors.initials: D
authors.lastname: Bryzek
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kmiecik
authors.forename: Danuta
authors.initials: D
authors.lastname: Mizgalska
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Maciag-Gudowska
authors.forename: Lindsey N
authors.initials: LN
authors.lastname: Shaw
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
mesh_terms: D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019610:Cytoprotection; D006460:Hemolysin Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D009154:Mutation / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis; D013203:Staphylococcal Infections / Q000276:immunology* / Q000635:transmission; D013211:Staphylococcus aureus / Q000276:immunology* / Q000472:pathogenicity; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D037521:Virulence Factors
chemical_list: D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D037521:Virulence Factors; C021091:staphylococcal alpha-toxin