Subject(s)
Corynebacterium/metabolism , Diphtheria Toxin/chemistry , Diphtheria Toxin/metabolism , Diphtheria/microbiology , Amino Acid Sequence , Diphtheria/drug therapy , Diphtheria/epidemiology , Female , Germany/epidemiology , Humans , Middle Aged , Molecular Sequence Data , Sequence Homology, Amino AcidABSTRACT
The virulence antigen (LcrV) of pathogenic yersiniae "silences" macrophages against stimulation with the TLR2-agonist zymosan A in a CD14/TLR2-dependent fashion via IL-10 induction. This pathogenically important "silencing" resembles TLR tolerance phenomena; in these, pre-exposure to a primary tolerizing TLR-agonist renders macrophages unresponsive to stimulation with a secondary challenging TLR-agonist which may involve either the same (TLR homotolerance) or a different TLR (TLR heterotolerance) as the primary TLR-agonist. Here, we show that rLcrV induces TLR homo- and heterotolerance against TLR2- or TLR4-agonists both in human and murine macrophages, respectively. The underlying mechanism of LcrV-induced tolerance is most likely not due to changes in TLR2- or TLR4 expression, but involves LcrV-mediated IL-10 production, since LcrV-induced TLR homo- and heterotolerance is highly impaired in IL-10(-/-) macrophages. Moreover, the involvement of IL-10 in TLR tolerance induction seems to be a more general phenomenon as shown by experiments using different TLR-agonists in IL-10(-/-) macrophages. Since LcrV acts as a secreted protein upon macrophages without requiring direct cell contact, as shown in transwell assays, we propose that yersiniae exploit IL-10-involving TLR tolerance mechanisms by the virulence factor LcrV.
Subject(s)
Antigens, Bacterial/immunology , Immune Tolerance/immunology , Interleukin-10/immunology , Membrane Glycoproteins/immunology , Receptors, Cell Surface/immunology , Yersinia Infections/immunology , Yersinia/immunology , Animals , Cells, Cultured , Female , Humans , Interleukin-10/metabolism , Lipopolysaccharide Receptors/immunology , Lipopolysaccharide Receptors/metabolism , Macrophages/immunology , Macrophages/metabolism , Macrophages/microbiology , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Mice , Pore Forming Cytotoxic Proteins , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Receptors, Immunologic/deficiency , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Toll-Like Receptor 2 , Toll-Like Receptor 4 , Toll-Like Receptors , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolism , Yersinia Infections/metabolism , Yersinia Infections/microbiologyABSTRACT
While Corynebacterium ulcerans can mimic classical diphtheria, extrapharyngeal infections are extremely rare. Sequencing of the diphtheria toxin (DT)-encoding tox gene of two C. ulcerans isolates from extrapharyngeal infections revealed differences from C. diphtheriae DT sequences, mainly in the translocation and receptor-binding domains. C. ulcerans supernatants were much less potent than supernatant from C. diphtheriae. A C. ulcerans DT-specific PCR is described below.
