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

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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.

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Acknowledgments

We thank Martin Oti for the helpful discussions. MJ and MGN were supported by an ERC Consolidator Grant (nr. 310372 to MGN). RvdL and MAH were supported by the Virgo Consortium, funded by the Dutch government (FES0908), and by the Netherlands Genomics Initiative (050-060-452). CW was supported by the ERC Advanced Grant, ERC-671274. XW was supported by NSFC 11101321 and NSFC 61263039 grants.

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The authors declare that they have no conflict of interest.

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    Authors and Affiliations

    1. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

      M. Jaeger, S.-C. Cheng, T. S. Plantinga, S. P. Smeekens, M. Oosting, X. Wang, L. A. B. Joosten, F. L. van de Veerdonk, B. J. Kullberg & M. G. Netea

    2. Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands

      R. van der Lee & M. A. Huynen

    3. Division of Infectious Diseases, Duke University Medical Center, Durham, NC, USA

      M. D. Johnson & J. R. Perfect

    4. Department of Clinical Research, Campbell University College of Pharmacy & Health Sciences, Buies Creek, NC, USA

      M. D. Johnson

    5. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

      V. Kumar & C. Wijmenga

    6. Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

      A. Ng & R. J. Xavier

    7. Broad Institute of MIT and Harvard University, Cambridge, MA, 02142, USA

      A. Ng & R. J. Xavier

    8. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany

      W. Barchet

    9. Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, 01605, USA

      K. Fitzgerald

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    Correspondence to M. G. Netea.

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    M. Jaeger, R. van der Lee, and S.-C. Cheng contributed equally to this work.

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    Jaeger, M., van der Lee, R., Cheng, SC. et al. The RIG-I-like helicase receptor MDA5 (IFIH1) is involved in the host defense against Candida infections. Eur J Clin Microbiol Infect Dis 34, 963–974 (2015). https://doi.org/10.1007/s10096-014-2309-2

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