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The CLEC7A Y238∗ variant and susceptibility to pneumonia : a prospective population-based cohort study and mechanistic investigation

Thofte, Oskar LU orcid ; Öhnström, Valdemar LU orcid ; Yamba, Linda Yamba LU orcid ; Memon, Ashfaque LU orcid ; Grundberg, Anton LU ; Su, Yu-Ching LU ; Slevogt, Hortense ; Zipfel, Peter F ; Scavenius, Carsten and Steimbrüch, Bruno LU , et al. (2026) In EBioMedicine 133. p.1-21
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... (More)

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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organization
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type
Contribution to journal
publication status
published
subject
in
EBioMedicine
volume
133
article number
106497
pages
1 - 21
publisher
Elsevier
external identifiers
  • pmid:42849178
ISSN
2352-3964
DOI
10.1016/j.ebiom.2026.106497
language
English
LU publication?
yes
additional info
Copyright © 2026 The Author(s). Published by Elsevier B.V. All rights reserved.
id
0fc7d139-28ea-457f-85e1-c4c2343bf340
date added to LUP
2026-10-12 08:00:29
date last changed
2026-10-12 08:16:36
@article{0fc7d139-28ea-457f-85e1-c4c2343bf340,
  abstract     = {{<p>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.</p><p>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<br>
 +/-, and Clec7a<br>
 -/- 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.<br>
 </p><p>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.</p><p>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.</p><p>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.</p>}},
  author       = {{Thofte, Oskar and Öhnström, Valdemar and Yamba, Linda Yamba and Memon, Ashfaque and Grundberg, Anton and Su, Yu-Ching and Slevogt, Hortense and Zipfel, Peter F and Scavenius, Carsten and Steimbrüch, Bruno and Leandersson, Karin and Håkansson, Anders P and Sundquist, Kristina and Melander, Olle and Blom, Anna M and Riesbeck, Kristian}},
  issn         = {{2352-3964}},
  language     = {{eng}},
  month        = {{10}},
  pages        = {{1--21}},
  publisher    = {{Elsevier}},
  series       = {{EBioMedicine}},
  title        = {{The CLEC7A Y238∗ variant and susceptibility to pneumonia : a prospective population-based cohort study and mechanistic investigation}},
  url          = {{http://dx.doi.org/10.1016/j.ebiom.2026.106497}},
  doi          = {{10.1016/j.ebiom.2026.106497}},
  volume       = {{133}},
  year         = {{2026}},
}