Calcineurin regulates innate antifungal immunity in neutrophils.
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 beta(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.
Greenblatt
Matthew B
MB
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Aliprantis
Antonios
A
Hu
Bella
B
Glimcher
Laurie H
LH
D000818:Animals; D000935:Antifungal Agents / Q000276:immunology*; D019703:Calcineurin / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002176:Candida albicans; D002177:Candidiasis / Q000453:epidemiology* / Q000276:immunology; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use; D004198:Disease Susceptibility; D006706:Homeostasis; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D051379:Mice; D009181:Mycoses / Q000453:epidemiology* / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology / Q000502:physiology; D011135:Polysaccharides, Bacterial / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology; D047071:beta-Glucans / Q000494:pharmacology
D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D011135:Polysaccharides, Bacterial; D047071:beta-Glucans; C038459:curdlan; D016572:Cyclosporine; D015054:Zymosan; D019703:Calcineurin