Louis Bernard, Fabrice Chrétien, Vincent Pedergnana, Christiane Vermylen, Davood Mansouri, Jean-Laurent Casanova, A. S. Brunel, Elisa Barbati, Jacques Reynes, Seyed Alireza Mahdaviani, Anne Puel, Fanny Lanternier, Jean-Jacques de Bruycker, Michèle Loop, Dimitri Van der Linden, Yatrika Koumar, Blandine Denis, Romain Lévy, Laurent Abel, Marie-Cécile Nassogne, Julie Peeters, Hélène Chaussade, Mélanie Migaud, Alejandro A. Schäffer, Olivier Lortholary, Noureddine Amazrine, Ariel de Selys, Capucine Picard, Guillaume Desoubeaux, Ilad Alavi Darazam, Mihai G. Netea, Luyan Liu, Sophie Martin, Olga Chatzis, Jean Vanclaire, Grégory Jouvion, Thomas S. Harrison, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Shahid Beheshti University, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Bretonneau, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Cliniques Universitaires Saint-Luc [Bruxelles], Clinique Saint-Jean [Bruxelles], Université Catholique de Louvain = Catholic University of Louvain (UCL), Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris], Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), National Institutes of Health [Bethesda] (NIH), Radboud University Medical Center [Nijmegen], Centre de Recherche du Centre Hospitalier Universitaire (CHU) [Saint-Justine, Montréal], Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), St George's, University of London, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Supported in part by the Rockefeller University, INSERM, Paris Descartes University, the St. Giles Foundation and l'Agence Nationale de la Recherche (grant GENCMCD no 11-BSV3-005-01 to A.P.), and a Translational Research grant from the Jeffrey Modell Foundation (to A.P.). This study also received funding from the French Government as part of the Investissement d'Avenir program, Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant no. ANR-10-LABX-62-IBEID). F.L. was supported by a grant from the CMIT (French Faculties College of Infectious Diseases) and INSERM., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-11-BSV3-0005,GENCMCD,Dissection génétique de la candidose cutanéo-muqueuse chronique chez l'homme(2011), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Université Catholique de Louvain (UCL), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherches Translationnelles sur le VIH et les maladies infectieuses (TransVIHMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 1 (UM1)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Universtié Yaoundé 1 [Cameroun]-Université de Montpellier (UM), St George‘s, University of London, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris] (IP), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de cardiologie pédiatrique, UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique, UCL - (SLuc) Service de neurologie pédiatrique, and UCL - (SLuc) Service de pédiatrie générale
Item does not contain fulltext BACKGROUND: Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained. OBJECTIVE: We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only. METHODS: Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species. Therefore we sequenced CARD9 in the 5 patients. RESULTS: All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R70W and Q289* for the 3 patients with Candida albicans-induced meningoencephalitis, R35Q for the patient with meningoencephalitis and colitis caused by Candida glabrata, and Q295* for the patient with Candida albicans-induced colitis. Regardless of their levels of mutant CARD9 protein, the patients' monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed C albicans, Saccharomyces cerevisiae, and Exophiala dermatitidis). CONCLUSION: Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency.