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ABSTRACT: Chromoblastomycosis is a chronic skin infection caused by the fungus Fonsecaea pedrosoi. Exploring the reasons underlying the chronic nature of F. pedrosoi infection in a murine model of chromoblastomycosis, we find that chronicity develops due to a lack of pattern recognition receptor (PRR) costimulation. F. pedrosoi was recognized primarily by C-type lectin receptors (CLRs), but not by Toll-like receptors (TLRs), which resulted in the defective induction of proinflammatory cytokines. Inflammatory responses to F. pedrosoi could be reinstated by TLR costimulation, but also required the CLR Mincle and signaling via the Syk/CARD9 pathway. Importantly, exogenously administering TLR ligands helped clear F. pedrosoi infection in vivo. These results demonstrate how a failure in innate recognition can result in chronic infection, highlight the importance of coordinated PRR signaling, and provide proof of the principle that exogenously applied PRR agonists can be used therapeutically.
Cell host & microbe 05/2011; 9(5):436-43. · 13.02 Impact Factor
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Matthew J Robinson,
Fabiola Osorio,
Marcela Rosas,
Rui P Freitas,
Edina Schweighoffer,
Olaf Gross,
J Sjef Verbeek,
Jürgen Ruland, Victor Tybulewicz,
Gordon D Brown,
Luis Ferreira Moita,
Philip R Taylor,
Caetano Reis e Sousa
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ABSTRACT: Innate immune cells detect pathogens via pattern recognition receptors (PRRs), which signal for initiation of immune responses to infection. Studies with Dectin-1, a PRR for fungi, have defined a novel innate signaling pathway involving Syk kinase and the adaptor CARD9, which is critical for inducing Th17 responses to fungal infection. We show that another C-type lectin, Dectin-2, also signals via Syk and CARD9, and contributes to dendritic cell (DC) activation by fungal particles. Unlike Dectin-1, Dectin-2 couples to Syk indirectly, through association with the FcRgamma chain. In a model of Candida albicans infection, blockade of Dectin-2 did not affect innate immune resistance but abrogated Candida-specific T cell production of IL-17 and, in combination with the absence of Dectin-1, decreased Th1 responses to the organism. Thus, Dectin-2 constitutes a major fungal PRR that can couple to the Syk-CARD9 innate signaling pathway to activate DCs and regulate adaptive immune responses to fungal infection.
Journal of Experimental Medicine 09/2009; 206(9):2037-51. · 13.85 Impact Factor
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Olaf Gross,
Hendrik Poeck,
Michael Bscheider,
Catherine Dostert,
Nicole Hannesschläger,
Stefan Endres,
Gunther Hartmann,
Aubry Tardivel,
Edina Schweighoffer, Victor Tybulewicz,
Attila Mocsai,
Jürg Tschopp,
Jürgen Ruland
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ABSTRACT: Fungal infections represent a serious threat, particularly in immunocompromised patients. Interleukin-1beta (IL-1beta) is a key pro-inflammatory factor in innate antifungal immunity. The mechanism by which the mammalian immune system regulates IL-1beta production after fungal recognition is unclear. Two signals are generally required for IL-1beta production: an NF-kappaB-dependent signal that induces the synthesis of pro-IL-1beta (p35), and a second signal that triggers proteolytic pro-IL-1beta processing to produce bioactive IL-1beta (p17) via Caspase-1-containing multiprotein complexes called inflammasomes. Here we demonstrate that the tyrosine kinase Syk, operating downstream of several immunoreceptor tyrosine-based activation motif (ITAM)-coupled fungal pattern recognition receptors, controls both pro-IL-1beta synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signalling for pro-IL-1beta synthesis selectively uses the Card9 pathway, inflammasome activation by the fungus involves reactive oxygen species production and potassium efflux. Genetic deletion or pharmalogical inhibition of Syk selectively abrogated inflammasome activation by C. albicans but not by inflammasome activators such as Salmonella typhimurium or the bacterial toxin nigericin. Nlrp3 (also known as NALP3) was identified as the critical NOD-like receptor family member that transduces the fungal recognition signal to the inflammasome adaptor Asc (Pycard) for Caspase-1 (Casp1) activation and pro-IL-1beta processing. Consistent with an essential role for Nlrp3 inflammasomes in antifungal immunity, we show that Nlrp3-deficient mice are hypersusceptible to Candida albicans infection. Thus, our results demonstrate the molecular basis for IL-1beta production after fungal infection and identify a crucial function for the Nlrp3 inflammasome in mammalian host defence in vivo.
Nature 05/2009; 459(7245):433-6. · 36.28 Impact Factor
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Bitao Liang,
Craig Workman,
Janine Lee,
Claude Chew,
Benjamin M Dale,
Lucrezia Colonna,
Marcella Flores,
Nianyu Li,
Edina Schweighoffer,
Steven Greenberg, Victor Tybulewicz,
Dario Vignali,
Raphael Clynes
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ABSTRACT: Lymphocyte activation gene-3 (LAG-3) is a CD4-related transmembrane protein expressed by regulatory T cells that binds MHC II on APCs. It is shown in this study that during Treg:DC interactions, LAG-3 engagement with MHC class II inhibits DC activation. MHC II cross-linking by agonistic Abs induces an ITAM-mediated inhibitory signaling pathway, involving FcgammaRgamma and ERK-mediated recruitment of SHP-1 that suppresses dendritic cell maturation and immunostimulatory capacity. These data reveal a novel ITAM-mediated inhibitory signaling pathway in DCs triggered by MHC II engagement of LAG-3, providing a molecular mechanism in which regulatory T cells may suppress via modulating DC function.
The Journal of Immunology 06/2008; 180(9):5916-26. · 5.79 Impact Factor
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Kevin M Dennehy,
Gerben Ferwerda,
Inês Faro-Trindade,
Elwira Pyz,
Janet A Willment,
Philip R Taylor,
Ann Kerrigan,
S Vicky Tsoni,
Siamon Gordon,
Friederike Meyer-Wentrup,
Gosse J Adema,
Bart-Jan Kullberg,
Edina Schweighoffer, Victor Tybulewicz,
Hector M Mora-Montes,
Neil A R Gow,
David L Williams,
Mihai G Netea,
Gordon D Brown
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ABSTRACT: Recognition of microbial components by germ-line encoded pattern recognition receptors (PRR) initiates immune responses to infectious agents. We and others have proposed that pairs or sets of PRR mediate host immunity. One such pair comprises the fungal beta-glucan receptor, Dectin-1, which collaborates through an undefined mechanism with Toll-like receptor 2 (TLR2) to induce optimal cytokine responses in macrophages. We show here that Dectin-1 signaling through the spleen tyrosine kinase (Syk) pathway is required for this collaboration, which can also occur with TLR4, 5, 7 and 9. Deficiency of either Syk or the TLR adaptor MyD88 abolished collaborative responses, which include TNF, MIP-1alpha and MIP-2 production, and which are comparable to the previously described synergy between TLR2 and TLR4. Collaboration of the Syk and TLR/MyD88 pathways results in sustained degradation of the inhibitor of kappaB (IkappaB), enhancing NFkappaB nuclear translocation. These findings establish the first example of Syk- and MyD88-coupled PRR collaboration, further supporting the concept that paired receptors collaborate to control infectious agents.
European Journal of Immunology 03/2008; 38(2):500-6. · 5.10 Impact Factor
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Kevin M. Dennehy,
Gerben Ferwerda,
Inês Faro-Trindade,
Elwira Pyż,
Janet A. Willment,
Philip R. Taylor,
Ann Kerrigan,
S. Vicky Tsoni,
Siamon Gordon,
Friederike Meyer-Wentrup,
Gosse J. Adema,
Bart-Jan Kullberg,
Edina Schweighoffer, Victor Tybulewicz,
Hector M. Mora-Montes,
Neil A. R. Gow,
David L. Williams,
Mihai G. Netea,
Gordon D. Brown Dr
[show abstract]
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ABSTRACT: Recognition of microbial components by germ-line encoded pattern recognition receptors (PRR) initiates immune responses to infectious agents. We and others have proposed that pairs or sets of PRR mediate host immunity. One such pair comprises the fungal β-glucan receptor, Dectin-1, which collaborates through an undefined mechanism with Toll-like receptor 2 (TLR2) to induce optimal cytokine responses in macrophages. We show here that Dectin-1 signaling through the spleen tyrosine kinase (Syk) pathway is required for this collaboration, which can also occur with TLR4, 5, 7 and 9. Deficiency of either Syk or the TLR adaptor MyD88 abolished collaborative responses, which include TNF, MIP-1α and MIP-2 production, and which are comparable to the previously described synergy between TLR2 and TLR4. Collaboration of the Syk and TLR/MyD88 pathways results in sustained degradation of the inhibitor of kB (IkB), enhancing NFkB nuclear translocation. These findings establish the first example of Syk- and MyD88-coupled PRR collaboration, further supporting the concept that paired receptors collaborate to control infectious agents.
European Journal of Immunology 01/2008; 38(2):500 - 506. · 5.10 Impact Factor
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Salomé LeibundGut-Landmann,
Olaf Gross,
Matthew J Robinson,
Fabiola Osorio,
Emma C Slack,
S Vicky Tsoni,
Edina Schweighoffer, Victor Tybulewicz,
Gordon D Brown,
Jürgen Ruland,
Caetano Reis e Sousa
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ABSTRACT: The C-type lectin dectin-1 binds to yeast and signals through the kinase Syk and the adaptor CARD9 to induce production of interleukin 10 (IL-10) and IL-2 in dendritic cells (DCs). However, whether this pathway promotes full DC activation remains unclear. Here we show that dectin-1-Syk-CARD9 signaling induced DC maturation and the secretion of proinflammatory cytokines, including IL-6, tumor necrosis factor and IL-23, but little IL-12. Dectin-1-activated DCs 'instructed' the differentiation of CD4+ IL-17-producing effector T cells (T(H)-17 cells) in vitro, and a dectin-1 agonist acted as an adjuvant promoting the differentiation of T(H)-17 and T helper type 1 cells in vivo. Infection with Candida albicans induced CARD9-dependent T(H)-17 responses to the organism. Our data indicate that signaling through Syk and CARD9 can couple innate to adaptive immunity independently of Toll-like receptor signals and that CARD9 is required for the development of T(H)-17 responses to some pathogens.
Nature Immunology 07/2007; 8(6):630-8. · 26.01 Impact Factor
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Salom|[eacute]| LeibundGut-Landmann,
Olaf Gro|[szlig,
Matthew J Robinson,
Fabiola Osorio,
Emma C Slack,
S Vicky Tsoni,
Edina Schweighoffer, Victor Tybulewicz,
Gordon D Brown,
J|[uuml]|rgen Ruland,
Caetano Reis e Sousa
[show abstract]
[hide abstract]
ABSTRACT: The C-type lectin dectin-1 binds to yeast and signals through the kinase Syk and the adaptor CARD9 to induce production of interleukin 10 (IL-10) and IL-2 in dendritic cells (DCs). However, whether this pathway promotes full DC activation remains unclear. Here we show that dectin-1–Syk–CARD9 signaling induced DC maturation and the secretion of proinflammatory cytokines, including IL-6, tumor necrosis factor and IL-23, but little IL-12. Dectin-1-activated DCs 'instructed' the differentiation of CD4+ IL-17-producing effector T cells (TH-17 cells) in vitro, and a dectin-1 agonist acted as an adjuvant promoting the differentiation of TH-17 and T helper type 1 cells in vivo. Infection with Candida albicans induced CARD9-dependent TH-17 responses to the organism. Our data indicate that signaling through Syk and CARD9 can couple innate to adaptive immunity independently of Toll-like receptor signals and that CARD9 is required for the development of TH-17 responses to some pathogens.
Nature Immunology 04/2007; 8(6):630-638. · 26.01 Impact Factor
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Eric Sebzda,
Chris Hibbard,
Shawn Sweeney,
Farhad Abtahian,
Natalie Bezman,
Gina Clemens,
Jonathan S Maltzman,
Lan Cheng,
Feiyan Liu,
Martin Turner, Victor Tybulewicz,
Gary A Koretzky,
Mark L Kahn
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ABSTRACT: Developmental studies support a common origin for blood and endothelial cells, while studies of adult angiogenic responses suggest that the hematopoietic system can be a source of endothelial cells later in life. Whether hematopoietic tissue is a source of endothelial cells during normal vascular development is unknown. Mouse embryos lacking the signaling proteins Syk and Slp-76 develop abnormal blood-lymphatic endothelial connections. Here we demonstrate that expression of GFPSlp-76 in a subset of hematopoietic cells rescues this phenotype, and that deficient cells confer focal vascular phenotypes in chimeric embryos consistent with a cell-autonomous mechanism. Endogenous Syk and Slp-76, as well as transgenic GFPSlp-76, are expressed in circulating cells previously proposed to be endothelial precursors, supporting a causal role for these cells. These studies provide genetic evidence for hematopoietic contribution to vascular development and suggest that hematopoietic tissue can provide a source of vascular endothelial progenitor cells throughout life.
Developmental Cell 10/2006; 11(3):349-61. · 14.03 Impact Factor
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ABSTRACT: The phagocytosis of pathogens is a critical event in host defense, not only for clearance of the invading microorganism, but also for the subsequent immune response. We have examined Dectin-1, a proinflammatory nonopsonic receptor for beta-glucans, and show that it mediates the internalization of beta-glucan-bearing ligands, including yeast particles. Although requiring tyrosine phosphorylation and the cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM)-like motif, uptake mediated by Dectin-1 was different from any previously reported phagocytic receptor and was not dependent on Syk-kinase in macrophages. Furthermore, intracellular trafficking of this receptor was influenced by the nature of the beta-glucan ligand, which has significance for the biologic activity of these immunomodulatory carbohydrates.
Blood 01/2005; 104(13):4038-45. · 9.90 Impact Factor
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Farhad Abtahian,
Anastasia Guerriero,
Eric Sebzda,
Min-Min Lu,
Rong Zhou,
Attila Mocsai,
Erin E Myers,
Bin Huang,
David G Jackson,
Victor A Ferrari, Victor Tybulewicz,
Clifford A Lowell,
John J Lepore,
Gary A Koretzky,
Mark L Kahn
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ABSTRACT: Lymphatic vessels develop from specialized endothelial cells in preexisting blood vessels, but the molecular signals that regulate this separation are unknown. Here we identify a failure to separate emerging lymphatic vessels from blood vessels in mice lacking the hematopoietic signaling protein SLP-76 or Syk. Blood-lymphatic connections lead to embryonic hemorrhage and arteriovenous shunting. Expression of slp-76 could not be detected in endothelial cells, and blood-filled lymphatics also arose in wild-type mice reconstituted with SLP-76-deficient bone marrow. These studies reveal a hematopoietic signaling pathway required for separation of the two major vascular networks in mammals.
Science 02/2003; 299(5604):247-51. · 31.20 Impact Factor
