Stenotrophomonas maltophilia contributes to smoking-related emphysema through IRF1-triggered PANoptosis of alveolar epithelial cells.

Cigarette smoke (CS), the main source of indoor air pollution and the primary risk factor for respiratory diseases, contains chemicals that can perturb microbiota through antibiotic effects. Although smoking induces a disturbance of microbiota in the lower respiratory tract, whether and how it contributes to initiation or promotion of emphysema are not well clarified. Here, we demonstrated an aberrant microbiome in lung tissue of patients with smoking-related COPD. We found that Stenotrophomonas maltophilia (S. maltophilia) was expanded in lung tissue of patients with smoking-related COPD. We revealed that S. maltophilia drives PANoptosis in alveolar epithelial cells and represses formation of alveolar organoids through IRF1 (interferon regulatory factor 1). Mechanistically, IRF1 accelerated transcription of ZBP1 (Z-DNA Binding Protein 1) in S. maltophilia-infected alveolar epithelial cells. Elevated ZBP1 served as a component of the PANoptosome, which triggered PANoptosis in these cells. By using of alveolar organoids infected by S. maltophilia, we found that targeting of IRF1 mitigated S. maltophilia-induced injury of these organoids. Moreover, the expansion of S. maltophilia and the expression of IRF1 negatively correlated with the progression of emphysema. Thus, the present study provides insights into the mechanism of lung dysbiosis in smoking-related COPD, and presents a potential target for mitigation of COPD progression.