Integrative analysis reveals ciliary dysfunction and compartmentalized LCN2 expression as distinct features of COVID-19

The unique pulmonary pathophysiology of COVID-19 compared with other respiratory viral infections remains poorly understood. We performed integrative bulk and single-cell RNA sequencing on bronchoalveolar lavage fluid (BALF) from patients with COVID-19 (n=24) or influenza (n=10) and healthy controls (n=10). While influenza primarily induced conventional inflammatory responses, COVID-19 triggered distinct microenvironmental remodeling characterized by a specific cilium-related gene signature (e.g., DNAH9, FOXJ1) and expansion of ciliated and airway epithelial cells. Cross-tissue comparison with peripheral blood mononuclear cells uncovered a compartmentalized immune response, particularly for Lipocalin-2 (LCN2), which showed opposite expression trends between the lung and systemic circulation. This study identifies ciliary dysfunction and epithelial-immune crosstalk as key features distinguishing COVID-19 from influenza and highlights epithelial-derived LCN2 as a robust, compartmentalized biomarker for disease severity. Overall design: This study utilized bulk RNA sequencing to characterize the transcriptomic landscape of the lower respiratory tract and systemic circulation during SARS-CoV-2 infection. BALF and PBMC samples were collected from COVID-19 patients, influenza patients (BALF only), and healthy controls. RNA was extracted using TRIzol reagent and sequenced via a commercial platform. Differential expression analysis was performed using the DESeq2 package, and batch effects across datasets were corrected using limma's removeBatchEffect function. The analysis focused on identifying COVID-19-specific signatures by comparing profiles against both healthy controls and influenza-infected samples.