caa a22 4500 606157476 CHVBK 20210128100614.0 cr unu---uuuuu 210128e20150501xx s 000 0 eng 10.1007/s10096-014-2309-2 doi (NATIONALLICENCE)springer-10.1007/s10096-014-2309-2 The RIG-I-like helicase receptor MDA5 ( IFIH1 ) is involved in the host defense against Candida infections [Elektronische Daten] [M. Jaeger, R. van der Lee, S.-C. Cheng, M. Johnson, V. Kumar, A. Ng, T. Plantinga, S. Smeekens, M. Oosting, X. Wang, W. Barchet, K. Fitzgerald, L. Joosten, J. Perfect, C. Wijmenga, F. van de Veerdonk, M. Huynen, R. Xavier, B. Kullberg, M. Netea] 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. Springer-Verlag Berlin Heidelberg, 2015 Candida albicans nationallicence Host defense nationallicence Candidemia nationallicence Genetic susceptibility nationallicence MDA5 nationallicence IFIH1 nationallicence Jaeger M. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut van der Lee R. Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands aut Cheng S.-C Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut Johnson M. Division of Infectious Diseases, Duke University Medical Center, Durham, NC, USA aut Kumar V. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands aut Ng A. Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut Plantinga T. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut Smeekens S. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut Oosting M. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut Wang X. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut Barchet W. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany aut Fitzgerald K. Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, 01605, Worcester, MA, USA aut Joosten L. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut Perfect J. Division of Infectious Diseases, Duke University Medical Center, Durham, NC, USA aut Wijmenga C. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands aut van de Veerdonk F. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut Huynen M. Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands aut Xavier R. Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut Kullberg B. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut Netea M. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut European Journal of Clinical Microbiology & Infectious Diseases Springer Berlin Heidelberg 34/5(2015-05-01), 963-974 0934-9723 34:5<963 2015 34 10096 https://doi.org/10.1007/s10096-014-2309-2 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10096-014-2309-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Jaeger M. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- van der Lee R. Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Cheng S.-C Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Johnson M. Division of Infectious Diseases, Duke University Medical Center, Durham, NC, USA aut NATIONALLICENCE 700 1- Kumar V. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Ng A. Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Plantinga T. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Smeekens S. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Oosting M. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Wang X. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Barchet W. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany aut NATIONALLICENCE 700 1- Fitzgerald K. Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, 01605, Worcester, MA, USA aut NATIONALLICENCE 700 1- Joosten L. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Perfect J. Division of Infectious Diseases, Duke University Medical Center, Durham, NC, USA aut NATIONALLICENCE 700 1- Wijmenga C. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands aut NATIONALLICENCE 700 1- van de Veerdonk F. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Huynen M. Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Xavier R. Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Kullberg B. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Netea M. Department of Internal Medicine (463), Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands aut NATIONALLICENCE 773 0- European Journal of Clinical Microbiology & Infectious Diseases Springer Berlin Heidelberg 34/5(2015-05-01), 963-974 0934-9723 34:5<963 2015 34 10096