Extrapulmonary Aspergillus infection in patients with CARD9 deficiency
Open accessAbstract
Invasive pulmonary aspergillosis is a life-threatening mycosis that only affects patients with immunosuppression, chemotherapy-induced neutropenia, transplantation, or congenital immunodeficiency. We studied the clinical, genetic, histological, and immunological features of 2 unrelated patients without known immunodeficiency who developed extrapulmonary invasive aspergillosis at the ages of 8 and 18. One patient died at age 12 with progressive intra-abdominal aspergillosis. The other patient had presented with intra-abdominal candidiasis at age 9, and developed central nervous system aspergillosis at age 18 and intra-abdominal aspergillosis at age 25. Neither patient developed Aspergillus infection of the lungs. One patient had homozygous M1I CARD9 (caspase recruitment domain family member 9) mutation, while the other had homozygous Q295X CARD9 mutation; both patients lacked CARD9 protein expression. The patients had normal monocyte and Th17 cell numbers in peripheral blood, but their mononuclear cells exhibited impaired production of proinflammatory cytokines upon fungus-specific stimulation. Neutrophil phagocytosis, killing, and oxidative burst against Aspergillus fumigatus were intact, but neither patient accumulated neutrophils in infected tissue despite normal neutrophil numbers in peripheral blood. The neutrophil tissue accumulation defect was not caused by defective neutrophil-intrinsic chemotaxis, indicating that production of neutrophil chemoattractants in extrapulmonary tissue is impaired in CARD9 deficiency. Taken together, our results show that CARD9 deficiency is the first known inherited or acquired condition that predisposes to extrapulmonary Aspergillus infection with sparing of the lungs, associated with impaired neutrophil recruitment to the site of infection.
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Defects in the CARD9 pathway predispose to chronic mucocutaneous candidiasis and disseminated aspergillosis.
“Defects in the CARD9 pathway have been found predisposing to chronic mucocutaneous candidiasis [28] and disseminated aspergillosis [29]”
From Race and ethnicity: Risk factors for fungal infections? (2023) · cites this paper as [29]
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- Authors
- Rieber, N., Gazendam, R. P., Freeman, A. F., Hsu, A. P., Collar, A. L., Sugui, J. A., Drummond, R. A., Rongkavilit, C., Hoffman, K., Henderson, C., Clark, L., Mezger, M., Swamydas, M., Engeholm, M., Schüle, R., Neumayer, B., Ebel, F., Mikelis, C. M., Pittaluga, S., Prasad, V. K., Singh, A., Milner, J. D., Williams, K. W., Lim, J. K., Kwon-Chung, K. J., Holland, S. M., Hartl, D., Kuijpers, T. W., & Lionakis, M. S.
- Affiliations
- München Klinik Schwabing (DE)
- Amsterdam UMC Location University of Amsterdam (NL)
- National Institutes of Health (US)
- Wayne State University (US)
- Icahn School of Medicine at Mount Sinai (US)
- University of Tübingen (DE)
- Hertie Institute for Clinical Brain Research (DE)
- Max-von-Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie (DE)
- Texas Tech University Health Sciences Center (US)
- Duke Medical Center (US)
- Corresponding author
- Hartl, Dominik
- Kuijpers, Taco W.
- Lionakis, Michail S.
- ORCID
- Rieber, Nikolaus
- Freeman, Alexandra F.
- Hsu, Amy P.
- Collar, Amanda L.
- Drummond, Rebecca A.
- Rongkavilit, Chokechai
- Hoffman, Kevin
- Henderson, Carolyn
- Mezger, Markus
- Swamydas, Muthulekha
- Schüle, Rebecca
- Neumayer, Bettina
- Ebel, Frank
- Mikelis, Constantinos M.
- Pittaluga, Stefania
- Prasad, Vinod K.
- Singh, Anurag
- Milner, Joshua D.
- Williams, Kelli W.
- Lim, Jean K.
- Kwon-Chung, Kyung J.
- Holland, Steven M.
- Hartl, Dominik
- Kuijpers, Taco W.
- Lionakis, Michail S.
- Venue
- JCI Insight
- Published
- 2016-10-20
- Volume
- 1
- Issue
- 17
- Pages
- e89890-e89890
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC5070961
- OpenAlex
- W2537967741
- Cited by
- 171
- References
- 39
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 12 · 2023: 14 · 2022: 16 · 2021: 14 · 2020: 26 · 2019: 19 · 2018: 25 · 2017: 20
- FWCI
- 13.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Deutsches Zentrum für Infektionsforschung
- Landsteiner Foundation for Blood Transfusion Research (LSBR 1706)
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (T32AI007647)
- NHLBI Division of Intramural Research
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- CARD9 deficiency, Aspergillus fumigatus, central nervous system aspergillosis, intra-abdominal candidiasis, neutrophil chemotaxis, proinflammatory cytokine production, Th17 cells, monocytes, inherited immunodeficiency
- MeSH terms
- Adolescent, Adult, Aspergillosis, Aspergillus fumigatus, Child, Homozygote, Humans, Lung, Male, Mutation, Neutrophils, Neutrophil Infiltration, CARD Signaling Adaptor Proteins
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