Dectin-1 Activation Controls Maturation of β-1,3-Glucan-containing Phagosomes

Mansour, Michael K.; Tam, Jenny M.; Khan, Nida S.; Seward, Michael W.; Davids, Peter J.; Puranam, Sravanthi; Sokolovska, Anna; Sykes, David B.; Dagher, Zeina; Becker, Christine; Tanne, Antoine; Reedy, Jennifer L.; Stuart, Lynda M.; Vyas, Jatin M.

doi:10.1074/jbc.m113.473223

Cited by 75 publications

(85 citation statements)

References 46 publications

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“…RAW 264.7 (RAW) macrophages were purchased from the American Type Cell Culture Collection (ATCC; Manassas, VA), C57BL/6 mouse immortalized macrophages were a gift from Douglas Golenbock (University of Massachusetts Medical School, Worcester, MA), and RAW cells expressing GFP-Dectin-1 were created as previously described (62). Primary bone marrow-derived macrophages (BMDMs) from C57BL/6, Dectin-1 Ϫ/Ϫ , and MyD88/TRIF Ϫ/Ϫ mice were obtained as previously described (78).…”

Section: Methodsmentioning

confidence: 99%

“…Given that exposure of ␤-1,3-glucan differs between spores and hyphae, we hypothesized that Dectin-1 would preferentially localize to sites of macrophage-hyphal interactions but not macrophage-spore interactions. To assess this hypothesis, we utilized macrophages that express a green fluorescent protein (GFP)-Dectin-1 (GD1) fusion protein (62). We stimulated GD1-expressing macrophages with E. rostratum for either 4 or 18 h. We performed live cell imaging of samples stained with calcofluor white (chitin stain) (Fig.…”

Section: Figmentioning

confidence: 99%

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The Carbohydrate Lectin Receptor Dectin-1 Mediates the Immune Response to Exserohilum rostratum

et al. 2017

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Dematiaceous molds are found ubiquitously in the environment and cause a wide spectrum of human disease, including infections associated with high rates of mortality. Despite this, the mechanism of the innate immune response has been less well studied, although it is key in the clearance of fungal pathogens. Here, we focus on Exserohilum rostratum, a dematiaceous mold that caused 753 infections during a multistate outbreak due to injection of contaminated methylprednisolone. We show that macrophages are incapable of phagocytosing Exserohilum. Despite a lack of phagocytosis, macrophage production of tumor necrosis factor alpha is triggered by hyphae but not spores and depends upon Dectin-1, a C-type lectin receptor. Dectin-1 is specifically recruited to the macrophage-hyphal interface but not the macrophage-spore interface due to differences in carbohydrate antigen expression between these two fungal forms. Corticosteroid and antifungal therapy perturb this response, resulting in decreased cytokine production. In vivo soft tissue infection in wild-type mice demonstrated that Exserohilum provokes robust neutrophilic and granulomatous inflammation capable of thwarting fungal growth. However, coadministration of methylprednisolone acetate results in robust hyphal tissue invasion and a significant reduction in immune cell recruitment. Our results suggest that Dectin-1 is crucial for macrophage recognition and the macrophage response to Exserohilum and that corticosteroids potently attenuate the immune response to this pathogen.

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Section: Methodsmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

The Carbohydrate Lectin Receptor Dectin-1 Mediates the Immune Response to Exserohilum rostratum

et al. 2017

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“…Slides were mounted on a Nikon Ti-E inverted microscope equipped with an EM-CCD camera (Hamamatsu, C9100-13). For live cell imaging, the microscopy chamber, housed in an environmental chamber, was humidified and set to 30°C [51]. Images were acquired using MetaMorph software (Molecular Devices).…”

Section: Methodsmentioning

confidence: 99%

Biguanides enhance antifungal activity against Candida glabrata

Feliu

Lord

et al. 2018

Virulence

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Candida spp. are the fourth leading cause of nosocomial blood stream infections in North America. Candida glabrata is the second most frequently isolated species, and rapid development of antifungal resistance has made treatment a challenge. In this study, we investigate the therapeutic potential of metformin, a biguanide with well-established action for diabetes, as an antifungal agent against C. glabrata. Both wild type and antifungal-resistant isolates of C. glabrata were subjected to biguanide and biguanide-antifungal combination treatment. Metformin, as well as other members of the biguanide family, were found to have antifungal activity against C. glabrata, with MIC50 of 9.34 ± 0.16 mg/mL, 2.09 ± 0.04 mg/mL and 1.87 ± 0.05 mg/mL for metformin, phenformin and buformin, respectively. We demonstrate that biguanides enhance the activity of several antifungal drugs, including voriconazole, fluconazole, and amphotericin, but not micafungin. The biguanide-antifungal combinations allowed for additional antifungal effects, with fraction inhibition concentration indexes ranging from 0.5 to 1. Furthermore, metformin was able to lower antifungal MIC50 in voriconazole and fluconazole-resistant clinical isolates of C. glabrata. We also observed growth reduction of C. glabrata with rapamycin and an FIC of 0.84 ± 0.09 when combined with metformin, suggesting biguanide action in C. glabrata may be related to inhibition of the mTOR complex. We conclude that the biguanide class has direct antifungal therapeutic potential and enhances the activity of select antifungals in the treatment of resistant C. glabrata isolates. These data support the further investigation of biguanides in the combination treatment of serious fungal infections.

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“…Dectin-1-mediated activation of the canonical NLRP3/caspase-1 inflammasome and subsequent production and processing of IL-1b requires pathogen internalization (Gringhuis et al, 2012). Dectin-1 is important for phagocytosis, phagolysosomal maturation, and cytotoxic responses (Li et al, 2011;Mansour et al, 2013;Strijbis et al, 2013;Ma et al, 2014). Dectin-1 activates macrophage-1 antigen in a pathway that involves the guanine nucleotide exchange factors Vav1 and Vav3, resulting in cytotoxic responses of neutrophils (Li et al, 2011).…”

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confidence: 99%