Toll-Like Receptor 2 Suppresses Immunity against Candida albicans through Induction of IL-10 and Regulatory T Cells

Department of Medicine,, University Medical Center St. Radboud, Nijmegen, The Netherlands.
The Journal of Immunology (Impact Factor: 4.92). 04/2004; 172(6):3712-8. DOI: 10.4049/jimmunol.172.6.3712
Source: PubMed


Toll-like receptor (TLR) 2 and TLR4 play a pivotal role in recognition of Candida albicans. We demonstrate that TLR2(-/-) mice are more resistant to disseminated Candida infection, and this is associated with increased chemotaxis and enhanced candidacidal capacity of TLR2(-/-) macrophages. Although production of the proinflammatory cytokines TNF, IL-1alpha, and IL-1beta is normal, IL-10 release is severely impaired in the TLR2(-/-) mice. This is accompanied by a 50% decrease in the CD4+CD25+ regulatory T (Treg) cell population in TLR2(-/-) mice. In vitro studies confirmed that enhanced survival of Treg cells was induced by TLR2 agonists. The deleterious role of Treg cells on the innate immune response during disseminated candidiasis was underscored by the improved resistance to this infection after depletion of Treg cells. In conclusion, C. albicans induces immunosuppression through TLR2-derived signals that mediate increased IL-10 production and survival of Treg cells. This represents a novel mechanism in the pathogenesis of fungal infections.

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    • "We were unable to detect a role for TLR-2 in TNF-␣ production by mast cells in response to C. albicans, a phenomenon previously described in murine peritoneal macrophages derived from TLR-2 knockout mice (Netea et al., 2004). However, we cannot discard that TLR-2 is activated in mast cells in response to C. albicans; it is possible that signaling through this PRR is involved in the production of other cytokines production, such as IL-10 (Netea et al., 2004). A recent study showed that mast cells were able to phagocytose C. albicans and produce ROS (Trevisan et al., 2014). "
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    ABSTRACT: Mast cells are crucial elements of the innate immune response. They reside in tissues that are commonly exposed to the external environment, such as the skin and mucosae, where they can rapidly detect the presence of pathogens and mount a potent inflammatory response that recruits other cellular effectors of the immune response. The contribution of mast cells to the immune response to viruses, bacteria, protozoa and multicellular parasites is well established, but there is scarce information about the role of these cells in fungal infections. In this study, we analyzed if mast cells are activated by Candida albicans and if the C-type lectin receptor Dectin-1 is involved in its recognition. We found that both yeasts and hyphae of C. albicans-induced mast cell degranulation and production of TNF-α, IL-6, IL-10, CCL3 and CCL4, while only yeasts were able to induce IL-1β. Mast cells also produced ROS after stimulation with both dimorphic phases of C. albicans. When mast cells were activated with yeasts and hyphae, they showed decreased expression of IκBα and increased presence of phosphorylated Syk. Blockade of the receptor Dectin-1, but not Toll-like receptor 2, decreased TNF-α production by mast cell in response to C. albicans. These results indicate that mast cells are capable of sensing the two phases of C. albicans, and suggest that mast cells participate as an early inductor of inflammation during the early innate immune response to this fungus. Copyright © 2015 Elsevier GmbH. All rights reserved.
    Immunobiology 05/2015; 220(9). DOI:10.1016/j.imbio.2015.05.005 · 3.04 Impact Factor
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    • "TLR2 is an important PRR for C. albicans recognition, activating innate immune responses both alone and in synergy with DECTIN-1 (Ferwerda et al., 2008). The deficiency of TLR2 influences susceptibility to systemic candidiasis in mice (Netea et al., 2004), but no studies have been performed in vaginal candidiasis models. The in silico analysis using homology modeling and conservation analysis suggests detrimental effects of the mutation on the function of the receptor. "
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    ABSTRACT: Objective: Approximately 5% of women suffer from recurrent vulvovaginal candidiasis (RVVC). It has been hypothesized that genetic factors play an important role in the susceptibility to RVVC. The aim of this study was to assess the effect of genetic variants of genes encoding for pattern recognition receptors (PRRs) on susceptibility to RVVC. Study design: For the study, 119 RVVC patients and 263 healthy controls were recruited. Prevalence of polymorphisms in five PRRs involved in recognition of Candida were investigated in patients and controls. In silico and functional studies were performed to assess their functional effects. Results: Single nucleotide polymorphisms (SNPs) in TLR1, TLR4, CLEC7A, and CARD9 did not affect the susceptibility to RVVC. In contrast, a non-synonymous polymorphism in TLR2 (rs5743704, Pro631His) increased the susceptibility to RVVC almost 3-fold. Furthermore, the TLR2 rs5743704 SNP had deleterious effects on protein function as assessed by in silico analysis, and in vitro functional assays suggested that it reduces production of IL-17 and IFNγ upon stimulation of peripheral blood mononuclear cells with Candida albicans. No effects were observed on serum mannose-binding lectin concentrations. Condensation: This study demonstrates the association of susceptibility to RVVC with genetic variation in TLR2, most likely caused by decreased induction of mucosal antifungal host defense. Conclusion: Genetic variation in TLR2 may significantly enhance susceptibility to RVVC by modulating host defense mechanisms against Candida. Additional studies are warranted to assess systematically the role of host genetic variation for susceptibility to RVVC.
    Frontiers in Microbiology 09/2014; 5:483. DOI:10.3389/fmicb.2014.00483 · 3.99 Impact Factor
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    • "Certain dermatophytes like T. rubrum produce substances e.g., the mannans associated with glycoproteins that diminish the immune response thus prevent complete eradication of the fungus [26]. Some fungi other than dermatophyte genera infecting the skin can induce immune-suppression through toll like receptor 2 (TLR2) mediated IL-10 release, and this leads to generation of CD4 + CD25 + T-regulatory cells with immunosuppressive potential [27]. It is suggested that T. rubrum has the ability to suppress the expression of toll like receptors in keratinocytes and Langerhans cells in dermis and epidermis necessary for stimulation of Th1-type cell response. "
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    ABSTRACT: The most prevalent skin infections are mainly caused by species of dermatophytes of the genera Trichophyton, Microsporum, and Epidermophyton that infect keratinized tissues and Stratum corneum of skin and hair. Besides proteases with putative role of kinases and other enzymes, immune modulators are abundantly secreted during infection as well. The molecular mechanism used by the dermatophytes to infect and counteract the host immune response is not well understood. The defense against infections basically depends on the host's immune responses to metabolites of the fungi, virulence of the infecting strain or species and anatomical site of the infection. The two aspects of the immune system, the immediate hypersensitivity and delayed-type hypersensitivity against dermatophytes may be crucial to the progression and severity of skin infection. Management of the infection through species identification and molecular diagnostic techniques as well as use of novel targeted drugs in addition to conventional anti-fungal compounds is of great importance in dealing with disease onsets and outbreaks. Here we reviewed the fungal skin infections elucidating their biologic and immunologic characteristics. Reaction to fungal invasion by the infected epithelial tissue on the host side is also discussed. Moreover, determinants of protective immunity and treatment options are focused that could confer long-lasting resistance to infection.
    Current Protein and Peptide Science 05/2014; 15:437-444. DOI:10.2174/1389203715666140512121349 · 3.15 Impact Factor
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