2. Academic Validation
  3. Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both

Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both

  • J Allergy Clin Immunol. 2015 Jun;135(6):1558-68.e2. doi: 10.1016/j.jaci.2014.12.1930.
Fanny Lanternier 1,  Seyed Alireza Mahdaviani 2,  Elisa Barbati 3,  Hélène Chaussade 4,  Yatrika Koumar 5,  Romain Levy 3,  Blandine Denis 6,  Anne-Sophie Brunel 5,  Sophie Martin 7,  Michèle Loop 8,  Julie Peeters 7,  Ariel de Selys 8,  Jean Vanclaire 8,  Christiane Vermylen 9,  Marie-Cécile Nassogne 10,  Olga Chatzis 7,  Luyan Liu 3,  Mélanie Migaud 3,  Vincent Pedergnana 3,  Guillaume Desoubeaux 11,  Gregory Jouvion 12,  Fabrice Chretien 13,  Ilad Alavi Darazam 14,  Alejandro A Schäffer 15,  Mihai G Netea 16,  Jean J De Bruycker 17,  Louis Bernard 4,  Jacques Reynes 5,  Noureddine Amazrine 18,  Laurent Abel 19,  Dimitri Van der Linden 7,  Tom Harrison 20,  Capucine Picard 21,  Olivier Lortholary 22,  Davood Mansouri 14,  Jean-Laurent Casanova 23,  Anne Puel 24
Affiliations

Affiliations

  • 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.
PMID: 25702837 DOI: 10.1016/j.jaci.2014.12.1930
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.

Keywords

Candida species; Inborn error of immunity; central nervous system; colitis; human; inherited CARD9 deficiency; invasive fungal diseases; primary immunodeficiency.

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