Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species–induced meningoencephalitis, colitis, or both
Fanny Lanternier
(1, 2, 3)
,
Seyed Alireza Mahdaviani
(4)
,
Elisa Barbati
(1, 3)
,
Hélène Chaussade
(5, 6)
,
Yatrika Koumar
(7, 8, 9)
,
Romain Levy
(1, 3)
,
Blandine Denis
(1, 2, 3)
,
Anne-Sophie Brunel
(8)
,
Sophie Martin
(10)
,
Michele Loop
(11)
,
Julie Peeters
(12)
,
Ariel de Selys
(11)
,
Jean Vanclaire
(11)
,
Christiane Vermylen
(10)
,
Marie-Cécile Nassogne
(10)
,
Olga Chatzis
(10)
,
Luyan Liu
(1, 3)
,
Melanie Migaud
(1, 3)
,
Vincent Pedergnana
(1, 3)
,
Guillaume Desoubeaux
(5, 13)
,
Grégory Jouvion
(14)
,
Fabrice Chretien
(14, 15)
,
Ilad Alavi Darazam
(4)
,
Alejandro Schäffer
(16)
,
Mihai G. Netea
(17)
,
Jean de Bruycker
(18)
,
Louis Bernard
(5)
,
Jacques Reynes
(8, 19)
,
Noureddine Amazrine
,
Laurent Abel
(1, 3)
,
Dimitri van Der Linden
(10)
,
Tom Harrison
(20)
,
Capucine Picard
(1, 21, 3)
,
Olivier Lortholary
(1, 2, 22)
,
Davood Mansouri
(4)
,
Jean-Laurent Casanova
(1, 21, 3)
,
Anne Puel
(1, 3)
1
IMAGINE - U1163 -
Imagine - Institut des maladies génétiques
2 Centre d'infectiologie Necker-Pasteur [CHU Necker]
3 UPD5 - Université Paris Descartes - Paris 5
4 Shahid Beheshti University
5 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
6 Hôpital Bretonneau
7 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
8 Département Maladies Infectieuses et Tropicales [CHRU Montpellier]
9 UM - Université de Montpellier
10 Cliniques Universitaires Saint-Luc [Bruxelles]
11 Clinique Saint-Jean [Bruxelles]
12 UCL - Université Catholique de Louvain = Catholic University of Louvain
13 PRPA - Pathologies Respiratoires : Protéolyse et Aérosolthérapie
14 Histopathologie humaine et Modèles animaux
15 Centre Hospitalier Sainte Anne [Paris]
16 NIH - National Institutes of Health [Bethesda, MD, USA]
17 Radboud University Medical Center [Nijmegen]
18 Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada]
19 TransVIHMI - Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes
20 St George's, University of London
21 Service d'immuno-hématologie pédiatrique [CHU Necker]
22 CNRMA - Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals
2 Centre d'infectiologie Necker-Pasteur [CHU Necker]
3 UPD5 - Université Paris Descartes - Paris 5
4 Shahid Beheshti University
5 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
6 Hôpital Bretonneau
7 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
8 Département Maladies Infectieuses et Tropicales [CHRU Montpellier]
9 UM - Université de Montpellier
10 Cliniques Universitaires Saint-Luc [Bruxelles]
11 Clinique Saint-Jean [Bruxelles]
12 UCL - Université Catholique de Louvain = Catholic University of Louvain
13 PRPA - Pathologies Respiratoires : Protéolyse et Aérosolthérapie
14 Histopathologie humaine et Modèles animaux
15 Centre Hospitalier Sainte Anne [Paris]
16 NIH - National Institutes of Health [Bethesda, MD, USA]
17 Radboud University Medical Center [Nijmegen]
18 Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada]
19 TransVIHMI - Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes
20 St George's, University of London
21 Service d'immuno-hématologie pédiatrique [CHU Necker]
22 CNRMA - Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals
Fanny Lanternier
- Fonction : Auteur
- PersonId : 974030
Seyed Alireza Mahdaviani
- Fonction : Auteur
- PersonId : 779164
- ORCID : 0000-0001-6224-4797
Sophie Martin
- Fonction : Auteur
- PersonId : 752871
- IdHAL : sophie-martin-roscoff
- ORCID : 0000-0002-1256-3674
- IdRef : 10770062X
Christiane Vermylen
- Fonction : Auteur
- PersonId : 908401
Vincent Pedergnana
- Fonction : Auteur
- PersonId : 174866
- IdHAL : vincent-pedergnana
- ORCID : 0000-0002-7852-5339
- IdRef : 175475547
Guillaume Desoubeaux
- Fonction : Auteur
- PersonId : 953179
- ORCID : 0000-0001-7945-9890
- IdRef : 130306711
Grégory Jouvion
- Fonction : Auteur
- PersonId : 951348
- ORCID : 0000-0003-0188-2554
- IdRef : 076698416
Ilad Alavi Darazam
- Fonction : Auteur
- PersonId : 793369
- ORCID : 0000-0002-4440-335X
Noureddine Amazrine
- Fonction : Auteur
Laurent Abel
- Fonction : Auteur
- PersonId : 756191
- ORCID : 0000-0001-7016-6493
- IdRef : 07779432X
Capucine Picard
- Fonction : Auteur
- PersonId : 758297
- ORCID : 0000-0001-8788-5056
- IdRef : 091572363
Olivier Lortholary
- Fonction : Auteur
- PersonId : 1208424
- ORCID : 0000-0002-8325-8060
Davood Mansouri
- Fonction : Auteur
- PersonId : 762966
- ORCID : 0000-0002-1927-7072
Jean-Laurent Casanova
- Fonction : Auteur
- PersonId : 756193
- ORCID : 0000-0002-7782-4169
- IdRef : 073388726
Résumé
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.