Single-Cell Mapping Uncovers CXCL11 as a Modulator of Mucus Production and Inflammation in COPD Airway Epithelial cells after Influenza A Virus Infection

Influenza A virus (IAV) is one of the main causes of exacerbations in chronic obstructive pulmonary disease (COPD), contributing to high morbidity and mortality. The airway epithelium is the main target, and it is responsible for initiating lung regeneration after acute lung injury. Evidence indicates that COPD epithelium has a delayed antiviral response; however, the underlying mechanisms and cellular drivers remain elusive. To address this, we characterized the response of healthy and COPD airway epithelial cells cultured in air-liquid interface (ALI) to IAV at single-cell resolution. To this end, we profiled 97.573 cells, identifying all main compartments of the airway epithelium. Cell type proportion analysis revealed a reduction in deuterosomal and ciliated cells and an increase in basal epithelial cells in COPD patients. Notably, after infection, we observed a significant enrichment of certain cell types, including epithelial cells, as well as an enrichment of specific cell states inside basal, club, suprabasal, ciliated, and goblet cells. Cell-cell communication analysis revealed that cellular communication networks induced by infection differed between healthy and COPD airways, with pathways including NF-κB and JAK/STAT being differentially regulated. CXCL11, a well-known secreted activator of both signaling pathways, was significantly upregulated in most cell types. Beyond its role in immune cell attraction, the effect of CXCL11 on the airway epithelium is not yet clear. Mechanistically, we found that stimulation with CXCL11 was associated with heightened mucus production at baseline and an impaired immune response upon infection. In conclusion, we identified CXCL11 as an important secreted mediator involved in the epithelial response to IAV, leading to increased mucus production and diminished immune response. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany