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The Janus face of ?-toxin: a potent mediator of cytoprotection in staphylococci-infected macrophages.

ABSTRACT: After phagocytosis by macrophages, Staphylococcus aureus evades killing in an ?-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 ?-toxin and a set of hla-deficient strains, we show that ?-toxin is critical for the induction of MCL-1 expression and the cytoprotection of infected macrophages. Extracellular or intracellular treatment of macrophages with ?-toxin alone did not induce cytoprotection conferred by increased Mcl-1, suggesting that the process is dependent on the production of ?-toxin by intracellular bacteria. The increased expression of MCL-1 in infected cells was associated with enhanced NF?B 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 ?-toxin. Thus, S. aureus recognition by intracellular receptors and/or activation of downstream pathways leading to Mcl-1 expression is facilitated by ?-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 ?-toxin, we propose a novel role for this agent in the protection of the intracellular niche, and further dissemination of staphylococci by infected macrophages.

SUBMITTER: Koziel J

PROVIDER: S-EPMC4348342 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The Janus face of α-toxin: a potent mediator of cytoprotection in staphylococci-infected macrophages.

Koziel Joanna J Chmiest Daniela D Bryzek Danuta D Kmiecik Katarzyna K Mizgalska Danuta D Maciag-Gudowska Agnieszka A Shaw Lindsey N LN Potempa Jan J

Journal of innate immunity 20141030 2

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 ...[more]

PMID: 25358860

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Project description:Genome-wide gene expression profiling allows for identification of genes involved in the defense response of the host against pathogens. As presented here, transcriptomic analysis and bioinformatics tools were applied in order to identify genes expressed in the mammary gland parenchyma of cows naturally infected with coagulase-positive and coagulase-negative Staphylococci.In cows infected with coagulase-positive Staphylococci, being in 1st or 2nd lactation, 1700 differentially expressed genes (DEGs) were identified. However, examination of the 3rd or 4th lactations revealed 2200 DEGs. Gene ontology functional classification showed the molecular functions of the DEGs overrepresented the activity of cytokines, chemokines, and their receptors. In cows infected with coagulase-negative Staphylococci, in the 1st or 2nd lactations 418 DEGs, while in the 3rd or 4th lactations, 1200 DEGs were identified that involved in molecular functions such as protein, calcium ion and lipid binding, chemokine activity, and protein homodimerization. Gene network analysis showed DEGs associated with inflammation, cell migration, and immune response to infection, development of cells and tissues, and humoral responses to infections caused by both types of Staphylococci.A coagulase-positive Staphylococci infection caused a markedly stronger host response than that of coagulase-negative, resulting in vastly increased DEGs. A significant increase in the expression of the FOS, TNF, and genes encoding the major histocompatibility complex proteins (MHC) was observed. It suggests these genes play a key role in the synchronization of the immune response of the cow's parenchyma against mastitis-causing bacteria. Moreover, the following genes that belong to several physiological pathways (KEGG pathways) were selected for further studies as candidate genes of mammary gland immune response for use in Marker Assisted Selection (MAS): chemokine signaling pathway (CCL2, CXCL5, HCK, CCR1), cell adhesion molecules (CAMs) pathway (BOLA-DQA2, BOLA-DQA1, F11R, ITGAL, CD86), antigen processing and presentation pathway (CD8A, PDIA3, LGMN, IFI30, HSPA1A), and NOD-like receptor signaling pathway (TNF, IL8, IL18, NFKBIA).

Dataset Information

The Janus face of ?-toxin: a potent mediator of cytoprotection in staphylococci-infected macrophages.

Publications

The Janus face of α-toxin: a potent mediator of cytoprotection in staphylococci-infected macrophages.

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