The Tyr238X dectin-1 polymorphism is a predisposing factor for mucosal <strong>Candida</strong> albicans infections but not candidemia Diana C. Rosentul 1,2 , Theo S. Plantinga 1,2 , Marije Oosting 1,2 , William K. Scott 3 , Digna R. Velez Edwards 4 , P. Brian Smith 5 , Barbara D. Alexander 5 , John C. Yang 6 , Gregory M. Laird 5 , Walter J. F. M. van der Velden 2,7 , Bart Ferwerda 1,2 , Annemiek B. van Spriel 2,8 , Gosse Adema 2,8 , Ton Feuth 2,9 , J. Peter Donnelly 1,2 , Gordon D. Brown 10 , Nicole M. A. Blijlevens 2,7 , Leo A.B. Joosten 1,2 , Jos W. M. van der Meer 1,2 , John R. Perfect 5 , Bart-Jan Kullberg 1,2 , Melissa D. Johnson 5,11 , Mihai G. Netea 1,2 1 Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; 2 Nijmegen Institute for <strong>Infection</strong>, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; 3 Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA; 4 Department of Obstetrics & Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA; 5 Duke University Medical Center, Durham, NC, USA; 6 National Jewish Health, Denver, CO, USA; 7 Department of Haematology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; 8 Department of Tumor Immunology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; 9 Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; 10 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; 11 Department of Clinical Research, Campbell University School of Pharmacy, Buies Creek, NC, USA. The genetic make up of innate immune genes is believed to play an important role for susceptibility to <strong>fungal</strong> infections. We recently described the Tyr238X dectin-1 single nucleotide polymorphism (SNP) as an important factor influencing susceptibility to vulvo-vaginal candidiasis and onychomycosis in a Dutch family with recurrent <strong>fungal</strong> infections. The aim of our studies was to assess the role of this polymorphism in the susceptibility to mucosal and systemic <strong>Candida</strong> albicans infections. To achieve this aim we have investigated the effect of this SNP in several cohorts of patients: -142 Dutch patients undergoing hematopoietic stem cells transplantation (HSCT). -331 Dutch and American candidemia patients and 351 non infected matched controls. Functional studies have shown that cells isolated from individuals heterozygous for the 238X allele had a lower cytokine production upon stimulation with <strong>Candida</strong>. The HSCT patients bearing the early stop variant of the dectin-1 gene presented a higher C. albicans oral an gastrointestinal colonization compared to those who were 78
wild type for the polymorphism and required higher amounts of fluconazole in order to avoid a disseminated invasion of the fungus. In contrast, no effect if the Tyr238X dectin-1 SNP on the susceptibility to candidemia and/or the clinical course of the infection was observed. In conclusion, the dectin-1 signaling pathway is non-redundant in mucosal immunity to C. albicans. The 238X allele results in a defective IL-6 and IL-17 response, but normal IFN-gamma, upon stimulation with C. albicans. A genetic deficiency of beta-glucan recognition has clear effect on the occurrence of mucosal <strong>Candida</strong> infections, but a minor impact on susceptibility to candidemia. We are grateful to the European Commission for funding the <strong>FINSysB</strong> Marie Curie Initial Training Network (PITN-GA-2008-214004). 79
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