Transcriptomic analysis reveals shared deregulated neutrophil responses in COVID-19 and idiopathic pulmonary fibrosis

Coronavirus disease 2019 (COVID-19) is a respiratory disease linked with deregulated immune responses, leading to hyperinflammation, acute respiratory distress syndrome, and pulmonary fibrosis, often with fatal outcomes. Neutrophils play a central role in COVID-19 pathogenesis, with elevated peripheral blood neutrophil counts correlating with disease severity. Despite extensive research, the molecular processes associated with neutrophil hyperactivation in COVID-19 remain elusive.

To investigate the molecular signatures underlying neutrophil-driven pathology, we conducted transcriptome analysis in neutrophils isolated from the peripheral blood of COVID-19 patients versus healthy individuals. To evaluate the specificity of identified neutrophil signatures in COVID-19, we extended our transcriptomic analysis to neutrophils from patients with idiopathic pulmonary fibrosis (IPF), a non-infectious fibrotic lung disease. Additionally, immunofluorescence staining was performed on lung biopsy specimens from IPF patients to validate transcriptomic findings at the tissue level.

Our analysis revealed significant transcriptional changes in COVID-19 neutrophils, particularly in pathways involved in immune regulation, inflammation, and antiviral responses. Additionally, pathways associated with autophagy and chromatin remodeling were upregulated, while translation-related processes were suppressed, indicating an increased predisposition for neutrophil extracellular trap (NET) release. This neutrophil transcriptional signature in COVID-19 appears to be associated with the previously reported deregulation of the Activin/Follistatin system in the periphery. Notably, a comparative transcriptomic analysis with neutrophils isolated from IPF patients revealed the induction of substantially overlapping inflammatory processes, suggesting common deregulated responses in COVID-19 and IPF. Consistently, significant NET formation, a hallmark of COVID-19-related inflammation, was observed within lung biopsies from IPF patients.

By delineating both shared and disease-specific molecular pathways, our findings validate the critical role of neutrophils in COVID-19 and IPF pathophysiology, highlighting their involvement in balancing the inflammatory response across diverse lung diseases.