Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection

Robinson, Matthew; Osorio, Fabiola; Rosas, Marcela; Freitas, Rui P.; Schweighoffer, Edina; Groß, Olaf; Verbeek, J. Sjef; Ruland, Jürgen; Tybulewicz, Victor L. J.; Brown, Gordon D.; Moita, Luís F.; Taylor, Philip Russel; Sousa, Caetano Reis e

doi:10.1084/jem.20082818

Cited by 416 publications

(308 citation statements)

References 63 publications

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“…Zymosan, which can activate both Dectin-1 and Dectin-2, increases the transcription and secretion of IL-12p70, IL-23, IL-6, and IL-1␤ by BMDC, which in turn promotes the development of Th1 and Th17 immune responses. Robinson et al found that BMDC from B6 mice required only 1 of the two Dectin receptors in order to make TNF-␣ and IL-10 in response to zymosan (83), implying that the function of the two receptors was redundant if a fungal particle is recognized by both receptors. Mutation of either receptor makes mice more susceptible to systemic Candida albicans infection, though this may depend on the strain of C. albicans used to infect the mice (31,84,85).…”

Section: Discussionmentioning

confidence: 99%

Neither Dectin-2 nor the Mannose Receptor Is Required for Resistance to Coccidioides immitis in Mice

et al. 2014

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We investigated the roles of the mannose receptor (MR) and Dectin-2 in resistance to pulmonary coccidioidomycosis in C57BL/6 (B6) mice and in the interaction of myeloid cells with spherules, using B6 mice with targeted mutations in Mrc1 and Clec4n. Spherules are the tissue form of Coccidioides, and we determined that the MR on bone marrow-derived dendritic cells (BMDC) was important for recognition of spherules (formalin-killed spherules [FKS]) and for secretion of interleukin 10 (IL-10) and proinflammatory cytokines in response to FKS by both elicited macrophages and BMDC. Infected MR knockout (KO) mice produced more IL-10 in their lungs than did B6 mice, and MR KO mice also made more protective Th-17 cytokines. In contrast to the MR, Dectin-2 was not required for recognition of FKS by BMDC or for the production of cytokines by BMDC in response to FKS. However, Dectin-2 KO was required for stimulation of elicited peritoneal macrophages. Despite that, lung cytokine levels were not significantly different in Dectin-2 KO mice and B6 mice 14 days after infection, except for IL-1␤, which was higher in Dectin-2 KO lungs. Although both Dectin-2 ؊/؊ and MR ؊/؊ myeloid cells had reduced proinflammatory cytokine responses to FKS in vitro, neither MR nor Dectin-2 deficiency reduced the resistance of B6 mice to pulmonary coccidioidomycosis.

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Section: Discussionmentioning

confidence: 99%

Neither Dectin-2 nor the Mannose Receptor Is Required for Resistance to Coccidioides immitis in Mice

et al. 2014

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“…25 However in contrast to dectin-1 which, during canonical signaling, interacts with Syk directly, dectin-2 induces signaling through Syk indirectly by association with the FcRg chain. 26 Blockade of dectin-2 expressed on DCs has been reported to reduce Th17 responses during systemic infection with C. albicans.…”

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confidence: 99%

Adaptive immune responses toCandida albicansinfection

2015

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“…However, immune defense mechanisms against Coccidioides infection in the extrapulmonary organs and tissues are poorly understood. MyD88 and Card9 are two cytosolic immune adaptors that transduce signals from IL-1 receptor/Toll-like receptors (TIR/TLRs) and C-type lectin receptors (CLRs), respectively, to bridge innate and adaptive immunity (20,(40)(41)(42)(43)(44)(45). We recently reported that MyD88-and Card9-mediated signaling pathways contribute to the development of vaccine-induced Th17 and Th1 immunity against pulmonary Coccidioides infection (18,19).…”

Section: Discussionmentioning

confidence: 99%

Card9- and MyD88-Mediated Gamma Interferon and Nitric Oxide Production Is Essential for Resistance to Subcutaneous Coccidioides posadasii Infection

2016

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Coccidioidomycosis is a potentially life-threatening respiratory disease which is endemic to the southwestern United States and arid regions of Central and South America. It is responsible for approximately 150,000 infections annually in the United States alone. Almost every human organ has been reported to harbor parasitic cells of Coccidioides spp. in collective cases of the disseminated form of this mycosis. Current understanding of the mechanisms of protective immunity against lung infection has been largely derived from murine models of pulmonary coccidioidomycosis. However, little is known about the nature of the host response to Coccidioides in extrapulmonary tissue. Primary subcutaneous coccidioidal infection is rare but has been reported to result in disseminated disease. Here, we show that activation of MyD88 and Card9 signal pathways are required for resistance to Coccidioides infection following subcutaneous challenge of C57BL/6 mice, which correlates with earlier findings of the protective response to pulmonary infection. MyD88 ؊/؊ and Card9 ؊/؊ mice recruited reduced numbers of T cells, B cells, and neutrophils to the Coccidioides-infected hypodermis compared to wild-type mice; however, neutrophils were dispensable for resistance to skin infection. Further studies have shown that gamma interferon (IFN-␥) production and activation of Th1 cells characterize resistance to subcutaneous infection. Furthermore, activation of a phagosomal enzyme, inducible nitric oxide synthase, which is necessary for NO production, is a requisite for fungal clearance in the hypodermis. Collectively, our data demonstrate that MyD88-and Card9-mediated IFN-␥ and nitric oxide production is essential for protection against subcutaneous Coccidioides infection.T wo species of Coccidioides, C. immitis and C. posadasii, are soilborne molds and the etiologic agents of coccidioidomycosis, a potentially life-threatening human respiratory disease that is also known as San Joaquin Valley fever. This pulmonary mycosis is endemic to the southwestern United States and certain arid regions of Mexico, as well as Central and South America (1). Recent evidence has revealed that C. posadasii occurs in Washington State, well north of the previously documented boundary of regions of endemicity for coccidioidal infections in the United States (2). Coccidioides is a diphasic pathogen, characterized by a saprobic phase that produces dry, air-dispersed, infectious spores from vegetative mycelia and a parasitic cycle which is unique among the medically important fungi (3). Inhaled spores grow isotropically in the lungs of the mammalian host to form the first generation of parasitic cells (spherule initials). The spherule initials continue to enlarge and differentiate into multinucleate spherules (Ͼ80 m in diameter). The cytoplasm of these coenocytes undergoes a process of segmentation by invagination of the inner spherule wall layer, followed by the formation of a multitude of endospores, each 2 to 10 m in diameter. Endospores also undergo isotropic...

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Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection

Cited by 416 publications

References 63 publications

Neither Dectin-2 nor the Mannose Receptor Is Required for Resistance to Coccidioides immitis in Mice

Neither Dectin-2 nor the Mannose Receptor Is Required for Resistance to Coccidioides immitis in Mice

Adaptive immune responses toCandida albicansinfection

Card9- and MyD88-Mediated Gamma Interferon and Nitric Oxide Production Is Essential for Resistance to Subcutaneous Coccidioides posadasii Infection

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