Calcineurin regulates innate antifungal immunity in neutrophils. Academic Article uri icon

Overview

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 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.

publication date

  • April 26, 2010

Research

keywords

  • Antifungal Agents
  • Calcineurin
  • Candidiasis
  • Mycoses
  • Neutrophils

Identity

PubMed Central ID

  • PMC2867274

Scopus Document Identifier

  • 77952311527

Digital Object Identifier (DOI)

  • 10.1084/jem.20092531

PubMed ID

  • 20421389

Additional Document Info

volume

  • 207

issue

  • 5