title: The RIG-I-like helicase receptor MDA5 (IFIH1) is involved in the host defense against Candida infections.
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.
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Jaeger
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Robin
authors.initials: R
authors.lastname: van der Lee
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Shih-Chin
authors.initials: SC
authors.lastname: Cheng
authors.affiliation: Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina, USA and Department of Clinical Research, Campbell University School of Pharmacy, Buies Creek, North Carolina, USA.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.|Broad Institute of MIT and Harvard University, Cambridge, MA 02142 USA.
authors.forename: Aylwin
authors.initials: A
authors.lastname: Ng
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Sanne P
authors.initials: SP
authors.lastname: Smeekens
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Oosting
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Leo A B
authors.initials: LAB
authors.lastname: Joosten
authors.affiliation: Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina, USA and Department of Clinical Research, Campbell University School of Pharmacy, Buies Creek, North Carolina, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Huynen
authors.affiliation: Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.|Broad Institute of MIT and Harvard University, Cambridge, MA 02142 USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.affiliation: Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000328:Adult; D000818:Animals; D002175:Candida / Q000276:immunology*; D058387:Candidemia / Q000276:immunology*; D002478:Cells, Cultured; D015331:Cohort Studies; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000378:metabolism*; D004198:Disease Susceptibility; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000382:microbiology; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide
chemical_list: C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1