Calcineurin Regulates Innate Antifungal Immunity in Neutrophils
| Title: | Calcineurin Regulates Innate Antifungal Immunity in Neutrophils |
| Author: |
Hu, Bella; Aliprantis, Antonios O.; Glimcher, Laurie Hollis; Greenblatt, Matthew Blake
Note: Order does not necessarily reflect citation order of authors. |
| 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. |
| Full Text & Related Files: |
2867274.pdf (4.247Mb; PDF) 
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| 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. |
| Published Version: | doi:10.1084/jem.20092531 |
| Other Sources: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867274/pdf/ |
| Terms of Use: | This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA |
| Citable link to this page: | http://nrs.harvard.edu/urn-3:HUL.InstRepos:6348645 |
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