Fanny Lanternier1, Seyed Alireza Mahdaviani2, Elisa Barbati3, Hélène Chaussade4, Yatrika Koumar5, Romain Levy3, Blandine Denis6, Anne-Sophie Brunel5, Sophie Martin7, Michèle Loop8, Julie Peeters7, Ariel de Selys8, Jean Vanclaire8, Christiane Vermylen9, Marie-Cécile Nassogne10, Olga Chatzis7, Luyan Liu3, Mélanie Migaud3, Vincent Pedergnana3, Guillaume Desoubeaux11, Gregory Jouvion12, Fabrice Chretien13, Ilad Alavi Darazam14, Alejandro A Schäffer15, Mihai G Netea16, Jean J De Bruycker17, Louis Bernard4, Jacques Reynes5, Noureddine Amazrine18, Laurent Abel19, Dimitri Van der Linden7, Tom Harrison20, Capucine Picard21, Olivier Lortholary22, Davood Mansouri14, Jean-Laurent Casanova23, Anne Puel24. 1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; Necker Pasteur Infectious Diseases Center, Necker Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Imagine Institute, Paris, France. 2. Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France. 4. Infectious Diseases Unit, Bretonneau Hospital, Tours, France. 5. Infectious Diseases Unit, Montpellier, France. 6. Paris Descartes University, Imagine Institute, Paris, France; Necker Pasteur Infectious Diseases Center, Necker Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Imagine Institute, Paris, France. 7. Pediatric Infectious Diseases Unit, Saint-Luc University Hospital, UCL, Brussels, Belgium. 8. Pediatric-Neonatology Unit, Saint-Jean Hospital, Brussels, Belgium. 9. Pediatric Hematology-Oncology Unit, Saint-Luc University Hospital, UCL, Brussels, Belgium. 10. Pediatric Neurology Unit, Saint-Luc University Hospital, UCL, Brussels, Belgium. 11. Parasitology-Mycology-Tropical Medicine Unit, Bretonneau Hospital, Center for the Study of Respiratory Diseases, INSERM U1100/Equipe 3 School of Medicine, Tours, France. 12. Human Histopathology and Animal Models, Infection and Epidemiology Department, Pasteur Institute, Paris, France. 13. Human Histopathology and Animal Models, Infection and Epidemiology Department, Pasteur Institute, Paris, France; Neuropathology Laboratory, Sainte-Anne Hospital, Paris, France. 14. Department of Clinical Immunology and Allergy, National Research Institute of Tuberculosis and Lung Diseases, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 15. National Center for Biotechnology Information, National Institutes of Health, Bethesda, Md. 16. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. 17. Immunology and Rheumatology Unit, Saint-Justine Hospital University Center, Montreal, Quebec, Canada. 18. Department of Neurosurgery, Tangier, Morocco. 19. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY. 20. Infection and Immunity Research Institute, Saint George's University of London, London, United Kingdom. 21. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; Department of Neurosurgery, Tangier, Morocco; Study Center for Immunodeficiency, Necker Hospital, AP-HP, Paris, France; Pediatric Hematology-Immunology Unit, Necker Hospital, AP-HP, Paris, France. 22. Paris Descartes University, Imagine Institute, Paris, France; Necker Pasteur Infectious Diseases Center, Necker Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Imagine Institute, Paris, France; National Reference Center for Invasive Mycoses and Antifungals, Molecular Mycology Unit, Pasteur Institute, Paris, France. 23. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Pediatric Hematology-Immunology Unit, Necker Hospital, AP-HP, Paris, France; Howard Hughes Medical Institute, New York, NY. 24. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France; Paris Descartes University, Imagine Institute, Paris, France. Electronic address: anne.puel@inserm.fr.
Abstract
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.
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.
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