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Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity
Open accessAbstract
The C-type lectin receptor Dectin-1 plays a pivotal role in antifungal immunity. In this study, the recently characterized human DECTIN1 Y238X early stop codon polymorphism leading to diminished Dectin-1 receptor activity was studied in relation to invasive aspergillosis susceptibility and severity in patients receiving hematopoietic stem cell transplantation. We found that the presence of the DECTIN1 Y238X polymorphism in either donors or recipients of hematopoietic stem cell transplantation increased susceptibility to aspergillosis, with the risk being highest when the polymorphism was present simultaneously in both donors and recipients (adjusted hazard ratio = 3.9; P = .005). Functionally, the Y238X polymorphism impaired the production of interferon-γ and interleukin-10 (IL-10), in addition to IL-1β, IL-6, and IL-17A, by human peripheral mononuclear cells and Dectin-1 on human epithelial cells contributed to fungal recognition. Mechanistically, studies on preclinical models of infection in intact or bone marrow-transplanted Dectin-1 knockout mice revealed that protection from infection requires a distinct, yet complementary, role of both donor and recipient Dectin-1. This study discloses Dectin-1 deficiency as a novel susceptibility factor for aspergillosis in high-risk patients and identifies a previously unsuspected role for Dectin-1 in antifungal immunity that is the ability to control both resistance and tolerance to the fungus contingent on hematopoietic/nonhematopoietic compartmentalization.
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Metadata
- Authors
- Cunha, C., Di Ianni, M., Bozza, S., Giovannini, G., Zagarella, S., Zelante, T., D'Angelo, C., Pierini, A., Pitzurra, L., Falzetti, F., Carotti, A., Perruccio, K., Latgé, J.-P., Rodrigues, F., Velardi, A., Aversa, F., Romani, L., & Carvalho, A.
- Affiliations
- University of Perugia (IT)
- Division of Hematology and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy;
- Institut Pasteur (FR)
- University of Minho (PT)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-12-09
- Volume
- 116
- Issue
- 24
- Pages
- 5394-5402
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2101233099
- Cited by
- 286
- References
- 44
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 15 · 2023: 9 · 2022: 16 · 2021: 23 · 2020: 16 · 2019: 15 · 2018: 17 · 2017: 18 · 2016: 23 · 2015: 21 · 2014: 20 · 2013: 19 · 2012: 29
- FWCI
- 15.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- Dectin-1, invasive aspergillosis, hematopoietic stem cell transplantation, antifungal immunity, C-type lectin receptors, interferon-gamma, IL-10, IL-17A, fungal recognition, bone marrow transplantation
- MeSH terms
- Dectin-1, Adolescent, Adult, Aged, Animals, Aspergillosis, Child, Disease Susceptibility, Epithelial Cells, Female, Fungi, Humans, Leukocytes, Mononuclear, Male, Membrane Proteins, Middle Aged, Nerve Tissue Proteins, Polymorphism, Genetic, Cytokines, Mice, Knockout, Hematopoietic Stem Cell Transplantation, Lectins, C-Type, Mice, Young Adult
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