Genetic and functional evidence identify Carboxypeptidase Q as a regulator of inflammation in respiratory infection

Background Host genetic factors may play a critical role in modulating severity of respiratory infections. However, previous studies have often been limited by pathogen heterogeneity and exposure misclassification. Results Utilizing a relatively homogenous Chinese population consists of 5,151 individuals with first-time infection by syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, we conducted a genome-wide association study and identified a novel locus at 8q22.1 (rs7817424, P = 4.60×10⁻⁸) associated with infection severity. Integrating results from gene mapping and the similarity-based gene prioritization suggested carboxypeptidase Q ( CPQ) gene as the likely causal gene. Single-cell RNA sequencing and transcription factor motif analyses revealed differential CPQ expression in lung immune cells, particularly tissue-resident macrophages and monocyte-derived macrophages, implicating innate immune pathways in severe disease. Functional experiments demonstrated that CPQ overexpression in THP-1 cells suppresses LPS-induced pro-inflammatory cytokines TNF-α and IL-6, while systemic inflammation mouse model showed reduced CPQ expression in lung tissues during severe pneumonia. Conclusions This study identifies establish CPQ as a novel genetic determinant for respiratory infection severity and uncover its previously unrecognized anti-inflammatory role, highlighting its potential as a therapeutic target for controlling hyperinflammatory responses in COVID-19 and beyond.