The RIG-I-like helicase receptor MDA5 (IFIH1) is involved in the host defense against Candida infections

  • M. Jaeger
  • R. van der Lee
  • S.-C. Cheng
  • M. D. Johnson
  • V. Kumar
  • A. Ng
  • T. S. Plantinga
  • S. P. Smeekens
  • M. Oosting
  • X. Wang
  • W. Barchet
  • K. Fitzgerald
  • L. A. B. Joosten
  • J. R. Perfect
  • C. Wijmenga
  • F. L. van de Veerdonk
  • M. A. Huynen
  • R. J. Xavier
  • B. J. Kullberg
  • M. G. Netea
Article

Abstract

The induction of host defense against Candida species is initiated by recognition of the fungi by pattern recognition receptors and activation of downstream pathways that produce inflammatory mediators essential for infection clearance. In this study, we present complementary evidence based on transcriptome analysis, genetics, and immunological studies in knockout mice and humans that the cytosolic RIG-I-like receptor MDA5 (IFIH1) has an important role in the host defense against C. albicans. Firstly, IFIH1 expression in macrophages is specifically induced by invasive C. albicans hyphae, and patients suffering from chronic mucocutaneous candidiasis (CMC) express lower levels of MDA5 than healthy controls. Secondly, there is a strong association between missense variants in the IFIH1 gene (rs1990760 and rs3747517) and susceptibility to systemic Candida infections. Thirdly, cells from Mda5 knockout mice and human peripheral blood mononuclear cells (PBMCs) with different IFIH1 genotypes display an altered cytokine response to C. albicans. These data strongly suggest that MDA5 is involved in immune responses to Candida infection. As a receptor for viral RNA, MDA5 until now has been linked to antiviral host defense, but these novel studies show unexpected effects in antifungal immunity as well. Future studies are warranted to explore the potential of MDA5 as a novel target for immunotherapeutic strategies.

Keywords

Candida albicans Host defense Candidemia Genetic susceptibility MDA5 IFIH1 

Supplementary material

10096_2014_2309_MOESM1_ESM.docx (7.9 mb)
ESM 1(DOCX 7.91 mb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • M. Jaeger
    • 1
  • R. van der Lee
    • 2
  • S.-C. Cheng
    • 1
  • M. D. Johnson
    • 3
    • 4
  • V. Kumar
    • 5
  • A. Ng
    • 6
    • 7
  • T. S. Plantinga
    • 1
  • S. P. Smeekens
    • 1
  • M. Oosting
    • 1
  • X. Wang
    • 1
  • W. Barchet
    • 8
  • K. Fitzgerald
    • 9
  • L. A. B. Joosten
    • 1
  • J. R. Perfect
    • 3
  • C. Wijmenga
    • 5
  • F. L. van de Veerdonk
    • 1
  • M. A. Huynen
    • 2
  • R. J. Xavier
    • 6
    • 7
  • B. J. Kullberg
    • 1
  • M. G. Netea
    • 1
  1. 1.Department of Internal Medicine (463)Radboud university medical centerNijmegenThe Netherlands
  2. 2.Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life SciencesRadboud university medical centerNijmegenThe Netherlands
  3. 3.Division of Infectious DiseasesDuke University Medical CenterDurhamUSA
  4. 4.Department of Clinical ResearchCampbell University College of Pharmacy & Health SciencesBuies CreekUSA
  5. 5.Department of GeneticsUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
  6. 6.Center for Computational and Integrative Biology and Gastrointestinal UnitMassachusetts General Hospital, Harvard Medical SchoolBostonUSA
  7. 7.Broad Institute of MIT and Harvard UniversityCambridgeUSA
  8. 8.Institute of Clinical Chemistry and Clinical PharmacologyUniversity Hospital Bonn, University of BonnBonnGermany
  9. 9.Division of Infectious Diseases and ImmunologyUniversity of Massachusetts Medical SchoolWorcesterUSA

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