Toll-like receptor 2 ligands on the staphylococcal cell wall downregulate superantigen-induced T cell activation and prevent toxic shock syndrome

FOCIS Centre for Clinical Immunology and Immunotherapeutics, Robarts Research Institute, London, Ontario, Canada.
Nature medicine (Impact Factor: 27.36). 07/2009; 15(6):641-8. DOI: 10.1038/nm.1965
Source: PubMed


Staphylococcal superantigens are pyrogenic exotoxins that cause massive T cell activation leading to toxic shock syndrome and death. Despite the strong adaptive immune response induced by these toxins, infections by superantigen-producing staphylococci are very common clinical events. We hypothesized that this may be partly a result of staphylococcal strains having developed strategies that downregulate the T cell response to these toxins. Here we show that the human interleukin-2 response to staphylococcal superantigens is inhibited by the simultaneous presence of bacteria. Such a downregulatory effect is the result of peptidoglycan-embedded molecules binding to Toll-like receptor 2 and inducing interleukin-10 production and apoptosis of antigen-presenting cells. We corroborated these findings in vivo by showing substantial prevention of mortality after simultaneous administration of staphylococcal enterotoxin B with either heat-killed staphylococci or Staphylococcus aureus peptidoglycan in mouse models of superantigen-induced toxic shock syndrome.

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Available from: S.M. Mansour Haeryfar, Jul 28, 2014
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    • "TLR2 and TLR1heterodimers, in turn, interact with triacylated lipopeptides, such as the synthetic agonist Pam3CSK4 [6]. TLR2/1 and TLR2/6 complexes have been linked to proinflammatory and anti-inflammatory responses, respectively [7], [8]. TLR2 recognition of agonists is also influenced by co-receptors and accessory molecules, such as CD14 [9], CD36 [10], MD-2 [11], lipopolysaccharide-binding protein (LBP) [12], CD11b-CD18 integrin [13], and ganglioside GD1a [14]. "
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    ABSTRACT: TLR2 plays a critical role in the protection against Paracoccidioides brasiliensis conferred by ArtinM administration. ArtinM, a D-mannose-binding lectin from Artocarpus heterophyllus, induces IL-12 production in macrophages and dendritic cells, which accounts for the T helper1 immunity that results from ArtinM administration. We examined the direct interaction of ArtinM with TLR2using HEK293A cells transfected with TLR2, alone or in combination with TLR1 or TLR6, together with accessory proteins. Stimulation with ArtinM induced NF-κB activation and interleukin (IL)-8 production in cells transfected with TLR2, TLR2/1, or TLR2/6. Murine macrophages that were stimulated with ArtinM had augmented TLR2 mRNA expression. Furthermore, pre-incubation of unstimulated macrophages with an anti-TLR2 antibody reduced the cell labeling with ArtinM. In addition, a microplate assay revealed that ArtinM bound to TLR2 molecules that had been captured by specific antibodies from a macrophages lysate. Notably,ArtinM binding to TLR2 was selectively inhibited when the lectin was pre-incubated with mannotriose. The biological relevance of the direct interaction of ArtinM with TLR2 glycans was assessed using macrophages from TLR2-KOmice, which produced significantly lower levels of IL-12 and IL-10 in response to ArtinM than macrophages from wild-type mice. Pre-treatment of murine macrophages with pharmacological inhibitors of signaling molecules demonstrated the involvement of p38 MAPK and JNK in the IL-12 production induced by ArtinM and the involvement ofPI3K in IL-10 production. Thus, ArtinM interacts directly with TLR2 or TLR2 heterodimers in a carbohydrate recognition-dependent manner and functions as a TLR2 agonist with immunomodulatory properties.
    PLoS ONE 06/2014; 9(6):e98512. DOI:10.1371/journal.pone.0098512 · 3.23 Impact Factor
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    • "To test this hypothesis, we used transgenic mice that express a chimeric MHC class II molecule consisting of HLA-DR-IEα and HLA-DRβ1*0401-1Eβ, which have a much higher affinity for superantigens than mouse MHC Class II molecules [23]. Therefore, unlike wild-type mice, the HLA-DR4 transgenic mice were demonstrated to develop TSS-like symptoms upon injection of a small amount of SEB (10 μg), following a sensitizing agent, D-galactosamine (D-gal) [7,24]. Chau et al. demonstrated that 100% lethality can be achieved after a single dose of 10 μg of SEB, following the sensitization with 30 mg of D-gal [24]. "
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    ABSTRACT: Toxic shock syndrome (TSS) is caused by an overwhelming host-mediated response to bacterial superantigens produced mainly by Staphylococcus aureus and Streptococcus pyogenes. TSS is characterized by aberrant activation of T cells and excessive release of pro-inflammatory cytokines ultimately resulting in capillary leak, septic shock, multiple organ dysfunction and high mortality rates. No therapeutic or vaccine has been approved by the U.S. Food and Drug Administration for TSS, and novel therapeutic strategies to improve clinical outcome are needed. Mesenchymal stromal (stem) cells (MSCs) are stromal cells capable of self-renewal and differentiation. Moreover, MSCs have immunomodulatory properties, including profound effects on activities of T cells and macrophages in specific contexts. Based on the critical role of host-derived immune mediators in TSS, we hypothesized that MSCs could modulate the host-derived proinflammatory response triggered by Staphylococcal enterotoxin B (SEB) and improve survival in experimental TSS. Effects of MSCs on proinflammatory cytokines in peripheral blood were measured in wild-type C57BL/6 mice injected with 50 mug of SEB. Effects of MSCs on survival were monitored in fatal experimental TSS induced by consecutive doses of D-galactosamine (10 mg) and SEB (10 mug) in HLA-DR4 transgenic mice. Despite significantly decreasing serum levels of IL-2, IL-6 and TNF induced by SEB in wild-type mice, human MSCs failed to improve survival in experimental TSS in HLA-DR4 transgenic mice. Similarly, a previously described downstream mediator of human MSCs, TNF-stimulated gene 6 (TSG-6), did not significantly improve survival in experimental TSS. Furthermore, murine MSCs, whether unstimulated or pre-treated with IFNgamma, failed to improve survival in experimental TSS. Our results suggest that the immunomodulatory effects of MSCs are insufficient to rescue mice from experimental TSS, and that mediators other than IL-2, IL-6 and TNF are likely to play critical mechanistic roles in the pathogenesis of experimental TSS.
    BMC Immunology 01/2014; 15(1):1. DOI:10.1186/1471-2172-15-1 · 2.48 Impact Factor
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    • "This combination of immunology and computational biology is sometimes referred to as “immunomics” or “computational immunology.” Bioinformatic techniques have been used to model how major histocompatibility complex (MHC) heterozygosity affects one’s interaction with bacteria (7) and the influenza virus (8), how host stress affects the pathogenicity of Pseudomonas aeruginosa in the human gut (9), and why the frequency of staphylococcal-induced toxic stress response is low even though infections by these bacteria are high (10). While some of these investigations require a user to have extensive knowledge of computational science, increasingly, bioinformatic tools are equipped with intuitive graphical user interfaces and so are more accessible to those without such a background. "
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    Frontiers in Immunology 12/2013; 4:416. DOI:10.3389/fimmu.2013.00416
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