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

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.

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.

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.

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.

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.