Calcineurin Regulates Innate Antifungal Immunity in Neutrophils

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Calcineurin Regulates Innate Antifungal Immunity in Neutrophils

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dc.contributor.author Hu, Bella
dc.contributor.author Aliprantis, Antonios O.
dc.contributor.author Glimcher, Laurie Hollis
dc.contributor.author Greenblatt, Matthew Blake
dc.date.accessioned 2012-01-04T20:52:27Z
dc.date.issued 2010
dc.identifier.citation Greenblatt, Matthew B., Antonios Aliprantis, Bella Hu, and Laurie H. Glimcher. 2010. Calcineurin regulates innate antifungal immunity in neutrophils. Journal of Experimental Medicine 207(5): 923-931. en_US
dc.identifier.issn 0022-1007 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:6348645
dc.description.abstract Patients taking immunosuppressive drugs, like cyclosporine A (CsA), that inhibit calcineurin are highly susceptible to disseminated fungal infections, although it is unclear how these drugs suppress resistance to these opportunistic pathogens. We show that in a mouse model of disseminated Candida albicans infection, CsA-induced susceptibility to fungal infection maps to the innate immune system. To further define the cell types targeted by CsA, we generated mice with a conditional deletion of calcineurin B (CnB) in neutrophils. These mice displayed markedly decreased resistance to infection with C. albicans, and both CnB-deficient and CsA-treated neutrophils showed a defect in the ex vivo killing of C. albicans. In response to the fungal-derived pathogen-associated molecular pattern zymosan, neutrophils lacking CnB displayed impaired up-regulation of genes (IL-10, Cox2, Egr1, and Egr2) regulated by nuclear factor of activated T cells, the best characterized CnB substrate. This activity was Myd88 independent and was reproduced by stimulation with the β(1,3) glucan curdlan, indicating that dectin-1, rather than toll-like receptors, is the upstream activator of calcineurin. Our results suggest that disseminated fungal infections seen in CsA-treated patients are not just a general consequence of systemic suppression of adaptive immunity but are, rather, a result of the specific blockade of evolutionarily conserved innate pathways for fungal resistance. en_US
dc.language.iso en_US en_US
dc.publisher Rockefeller University Press en_US
dc.relation.isversionof doi:10.1084/jem.20092531 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867274/pdf/ en_US
dash.license LAA
dc.title Calcineurin Regulates Innate Antifungal Immunity in Neutrophils en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Journal of Experimental Medicine en_US
dash.depositing.author Aliprantis, Antonios O.
dc.date.available 2012-01-04T20:52:27Z
dash.affiliation.other SPH^Immunology and Infectious Diseases Immunology en_US
dash.affiliation.other HMS^Stipendees - Enrichment Programs Stip en_US
dash.affiliation.other HMS^Stipendees - MD-PhD en_US
dash.affiliation.other HMS^Stipendees - Div of Medical Sciences en_US
dash.affiliation.other SPH^Immunology and Infectious Diseases Immunology en_US
dash.affiliation.other SPH^Immunology and Infectious Diseases TPH en_US
dash.affiliation.other HMS^Medicine-Brigham and Women's Hospital en_US

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