Klebsiella pneumoniae aggravates lung injury through ethanol production

Abstract Klebsiella pneumoniae, a major pathogen leading to severe pneumonia, causes clinical complications in nosocomial and community-acquired infections. We have previously reported that high alcohol-producing K. pneumoniae (HiAlc Kpn) in the gut microbiome are strongly associated with nonalcoholic fatty liver disease (NAFLD) owing to the excess endogenous alcohol production. In the present study, we discovered that Kpn isolated from sputum and bronchoalveolar fluid (BALF) of patients with pneumoniae and chronic obstructive pulmonary disease (COPD) could also produce excess ethanol. In a murine model, HiAlc Kpn aggravated lung injury of mice with acute infection comparing with alcohol dehydrogenase gene-knockout mutant. A single-cell sequencing transcriptome analysis showed that resistin like gamma (Retnlg) neutrophil played a critical role during acute infection. The HiAlc Kpn inactivated Retnlg neutrophils in an ethanol production-dependent manner in mice, which counteract immune defense possibly through down-regulating pyrimidine and modifying DNA methylation. Furthermore, data also showed that HiAlc Kpn inhibited interleukin 1 receptor antagonist (IL1RN) gene expression by neutrophils, thereby activating IL-1β to orchestrate immune responses. Understanding functions of Retnlg neutrophils and IL-1β release in the context of HiAlc Kpn and host interactions are essential for developing novel therapeutic strategies.