CARD9 controls a non-TLR signaling pathway for innate anti-fungal immunity

III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
Nature (Impact Factor: 41.46). 09/2006; 442(7103):651-6. DOI: 10.1038/nature04926
Source: PubMed

ABSTRACT Fungal infections are increasing worldwide due to the marked rise in immunodeficiencies including AIDS; however, immune responses to fungi are poorly understood. Dectin-1 is the major mammalian pattern recognition receptor for the fungal component zymosan. Dectin-1 represents the prototype of innate non-Toll-like receptors (TLRs) containing immunoreceptor tyrosine-based activation motifs (ITAMs) related to those of adaptive antigen receptors. Here we identify Card9 as a key transducer of Dectin-1 signalling. Although being dispensable for TLR/MyD88-induced responses, Card9 controls Dectin-1-mediated myeloid cell activation, cytokine production and innate anti-fungal immunity. Card9 couples to Bcl10 and regulates Bcl10-Malt1-mediated NF-kappaB activation induced by zymosan. Yet, Card9 is dispensable for antigen receptor signalling that uses Carma1 as a link to Bcl10-Malt1. Thus, our results define a novel innate immune pathway and indicate that evolutionarily distinct ITAM receptors in innate and adaptive immune cells use diverse adaptor proteins to engage selectively the conserved Bcl10-Malt1 module.

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Available from: Tim D Sparwasser, Sep 26, 2015
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    • "CARD9 is an important part of the pathway engaged by the pattern recognition receptor Dectin-1, which is responsible for initiating many innate immune responses to fungal elements, including, ultimately, the development of Th17 cells as discussed previously.17 Consistent with its essential role as a “danger signal” capable of recognizing Candida-derived fungal elements AR mutations in Dectin-1 and CARD9 have also been associated with the CMC phenotype. "
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    ABSTRACT: As immunologists, we are frequently asked to evaluate patients with recurrent infections. These infections can provide us with clues regarding what pathways might be aberrant in a given patient, e.g., specific pyogenic bacteria with Toll-like receptor problems, atypical mycobacteria with interferon gamma receptor autoantibodies, and Candida/staphylococcal infections with cellular immune abnormalities. We present a 55-year-old man who presented to our immunology clinic with onychodystrophy of the toenails and fingernails and recurrent oral‐esophageal candidiasis. The differential diagnosis for recurrent yeast infections is complex and includes usual suspects as well as some that are not as straightforward.
    Allergy and Asthma Proceedings 10/2014; 35(5). DOI:10.2500/aap.2014.35.3776 · 3.06 Impact Factor
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    • "CARD9 is an adaptor molecule mediating signals induced by DECTIN-1, but also other CLRs. Its role in antifungal immunity has been demonstrated both in knock-out mouse studies (Gross et al., 2006), as well as by the increased susceptibility to severe fungal infections in patients defective in this molecule due to an early stop codon in position Gln295Stop (Glocker et al., 2009). However, this mutation is rare and has not been reported in other individuals. "
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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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    • "Receptor ligation upregulates Spleen tyrosine kinase (SYK) and activates Protein Kinase C delta which phosphorylates Thr231 in CARD9 [12]. This causes formation of a CARD9/B Cell lymphoma 10 (Bcl-10)/Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) 'signalosome' which activates NF-jB [10] [13]. CARD9 is also involved in NF-jB signalling downstream of the Retinoic acid-inducible gene I receptor (RIG-1) family [14]. "
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    ABSTRACT: NOD2 activation by muramyl dipeptide causes a proinflammatory immune response in which the adaptor protein CARD9 works synergistically with NOD2 to drive p38 and c-Jun N-terminal kinase (JNK) signalling. To date the nature of the interaction between NOD2 and CARD9 remains undetermined. Here we show that this interaction is not mediated by the CARDs of NOD2 and CARD9 as previously suggested, but that NOD2 possesses two interaction sites for CARD9; one in the CARD-NACHT linker and one in the NACHT itself. Structured summary of protein interactions: NOD2 physically interacts with CARD9 by anti tag coimmunoprecipitation (View interaction) (C) 2014 The Authors. Published by Elsevier B.V.
    FEBS Letters 06/2014; 588(17). DOI:10.1016/j.febslet.2014.06.035 · 3.17 Impact Factor
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