The

Summary: 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.