The CLEC7A Y238∗ variant and susceptibility to pneumonia: a prospective population-based cohort study and mechanistic investigation.
11 affiliations
- 1Clinical Microbiology, Department of Translational Medicine, Faculty of Medicine, Lund University, Malmö, Sweden.
- 2Clinical Microbiology, Department of Translational Medicine, Faculty of Medicine, Lund University, Malmö, Sweden; Department of Clinical Microbiology, Infection Control and Prevention, Skåne University Hospital, Lund, Sweden.
- 3Center for Primary Health Care Research, Lund University, Region Skåne, Malmö, Sweden; Skåne University Hospital, University Clinic Primary Care, Region Skåne, Malmö, Sweden.
- 4Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, German Center for Lung Research (DZL), BREATH, Hannover, Germany; Respiratory Infection Dynamics Group, Helmholtz Centre for Infection Research, Braunschweig, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
- 5Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany.
- 6Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
- 7Cancer Immunology, Department of Translational Medicine, Faculty of Medicine, Lund University, Malmö, Sweden.
- 8Experimental Infection Medicine, Department of Translational Medicine, Faculty of Medicine, Lund University, Malmö, Sweden.
- 9Department of Emergency and Internal Medicine, Skåne University Hospital, Malmö, Sweden; Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Malmö, Sweden.
- 10Protein Chemistry, Department of Translational Medicine, Faculty of Medicine, Lund University, Malmö, Sweden; Department of Clinical Chemistry and Pharmacology, Skåne University Hospital, Malmö, Sweden.
- 11Clinical Microbiology, Department of Translational Medicine, Faculty of Medicine, Lund University, Malmö, Sweden; Department of Clinical Microbiology, Infection Control and Prevention, Skåne University Hospital, Lund, Sweden. Electronic address: [email protected].
Abstract
Background
DECTIN-1, a C-type lectin receptor encoded by CLEC7A, mediates antifungal immunity, but its antibacterial role remains unclear. We investigated, using human genetic and animal studies, whether the common loss-of-function CLEC7A Y238∗ variant (rs16910526) influences susceptibility to bacterial respiratory infection, and sought to identify the bacterial ligand mediating DECTIN-1 recognition.Methods
We analysed Y238∗ and pneumonia risk in the Malmö Diet and Cancer Study, a prospective Swedish cohort, using Cox models with age as timescale (28,126 participants, 5493 events; 26,601 and 5190 fully adjusted) over a mean 17·3 years of follow-up. We challenged wild-type, Clec7a+/-, and Clec7a-/- mice with Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi). Affinity proteomics, ELISA, flow cytometry, and NF-κB reporter assays identified and validated the ligand.Findings
Y238∗ carriers had elevated pneumonia risk in adjusted Cox models (HR 1·12, 95% CI 1·04-1·20; p = 0·002; concordant competing-risk sHR 1·12, 1·04-1·20). Clec7a-deficient mice showed gene-dose-dependent impairment of S. pneumoniae clearance, impaired NTHi clearance, and blunted cytokine responses. Affinity pull-down identified elongation factor Tu (EF-Tu) as a DECTIN-1 ligand that bound the carbohydrate-recognition domain and activated NF-κB signalling when clustered; orthologues from four bacterial species also bound.Interpretation
These findings support a role for DECTIN-1 in pulmonary antibacterial defence and suggest that inherited deficiency increases pneumonia susceptibility in humans. EF-Tu is a candidate ligand that provides mechanistic support for the association.Funding
Swedish Research Council, Knut and Alice Wallenberg Foundation, Swedish Heart Lung Foundation, Swedish Government Funds for Clinical Research (ALF), Skåne County Council's Research and Development Foundation.
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BibTeX
@article{thofte2026clec7a,
title = {{The CLEC7A Y238∗ variant and susceptibility to pneumonia: a prospective population-based cohort study and mechanistic investigation.}},
author = {Oskar Thofte and Valdemar Öhnström and Linda Yamba Yamba and Ashfaque Memon and Anton Grundberg and Yu-Ching Su and Hortense Slevogt and Peter F Zipfel and Carsten Scavenius and Bruno Steimbrüch and Karin Leandersson and Anders P Håkansson and Kristina Sundquist and Olle Melander and Anna M Blom and Kristian Riesbeck},
journal = {EBioMedicine},
year = {2026},
month = oct,
doi = {10.1016/j.ebiom.2026.106497},
url = {https://europepmc.org/article/MED/42849178},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - The CLEC7A Y238∗ variant and susceptibility to pneumonia: a prospective population-based cohort study and mechanistic investigation.
AU - Oskar Thofte
AU - Valdemar Öhnström
AU - Linda Yamba Yamba
AU - Ashfaque Memon
AU - Anton Grundberg
AU - Yu-Ching Su
AU - Hortense Slevogt
AU - Peter F Zipfel
AU - Carsten Scavenius
AU - Bruno Steimbrüch
AU - Karin Leandersson
AU - Anders P Håkansson
AU - Kristina Sundquist
AU - Olle Melander
AU - Anna M Blom
AU - Kristian Riesbeck
PY - 2026
DA - 2026/10/08
JO - EBioMedicine
DO - 10.1016/j.ebiom.2026.106497
UR - https://europepmc.org/article/MED/42849178
AB - Background DECTIN-1, a C-type lectin receptor encoded by CLEC7A, mediates antifungal immunity, but its antibacterial role remains unclear. We investigated, using human genetic and animal studies, whether the common loss-of-function CLEC7A Y238∗ variant (rs16910526) influences susceptibility to bacterial respiratory infection, and sought to identify the bacterial ligand mediating DECTIN-1 recognition.Methods We analysed Y238∗ and pneumonia risk in the Malmö Diet and Cancer Study, a prospective Swedish cohort, using Cox models with age as timescale (28,126 participants, 5493 events; 26,601 and 5190 fully adjusted) over a mean 17·3 years of follow-up. We challenged wild-type, Clec7a+/-, and Clec7a-/- mice with Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi). Affinity proteomics, ELISA, flow cytometry, and NF-κB reporter assays identified and validated the ligand.Findings Y238∗ carriers had elevated pneumonia risk in adjusted Cox models (HR 1·12, 95% CI 1·04-1·20; p = 0·002; concordant competing-risk sHR 1·12, 1·04-1·20). Clec7a-deficient mice showed gene-dose-dependent impairment of S. pneumoniae clearance, impaired NTHi clearance, and blunted cytokine responses. Affinity pull-down identified elongation factor Tu (EF-Tu) as a DECTIN-1 ligand that bound the carbohydrate-recognition domain and activated NF-κB signalling when clustered; orthologues from four bacterial species also bound.Interpretation These findings support a role for DECTIN-1 in pulmonary antibacterial defence and suggest that inherited deficiency increases pneumonia susceptibility in humans. EF-Tu is a candidate ligand that provides mechanistic support for the association.Funding Swedish Research Council, Knut and Alice Wallenberg Foundation, Swedish Heart Lung Foundation, Swedish Government Funds for Clinical Research (ALF), Skåne County Council's Research and Development Foundation.
SN - 2352-3964
ER -