Project description:Klebsiella pneumoniae liver abscess (KPLA) is a severe bacterial infection complicated by intrahepatic thrombophlebitis and extrahepatic metastatic infections, leading to high mortality rates. This study investigates the role of neutrophil extracellular traps (NETs) in endothelial injury and disease progression in KPLA. Our findings demonstrate that C3 deposition on NETs significantly contributes to endothelial damage. In a KPLA mouse model, increased C3 levels were observed in the liver, with NETs carrying substantial amounts of C3, disrupting the endothelial barrier and exacerbating liver injury. Treatment with the C3 inhibitor AMY-101 reduced C3 deposition on NETs, alleviated endothelial damage, significantly improved survival, and reduced extrahepatic dissemination, inflammatory infiltration, and lung injury while also suppressing systemic inflammation. Molecular analysis revealed that the TLR4-PI3Kα-AKT signaling pathway is crucial in K. pneumoniae-induced NET formation. Our findings underscore the pivotal role of C3 in NET-mediated endothelial damage and the pathogenesis of KPLA. Thus, targeting C3 deposition on NETs may be a promising therapeutic strategy to reduce endothelial injury, thrombosis, and extrahepatic infections in KPLA without compromising neutrophil antimicrobial function.
Project description:Klebsiella pneumoniae is an arising threat to human health. However, host immune responses in response to this bacterium remain to be elucidated. The goal of this study was to identify the dominant host immune responses associated with Klebsiella pneumoniae pulmonary infection. Pulmonary mRNA profiles of 6-8-weeks-old BALB/c mice infected with/without Klebsiella pneumoniae were generated by deep sequencing using Illumina Novaseq 6000. qRT–PCR validation was performed using SYBR Green assays. Using KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis, we identified several immune associated pathways, including complement and coagulation cascades, Toll-like receptor signaling pathway, Rap1 signaling pathway, chemokine signaling pathway, TNF signaling pathway, phagosome and NOD-like receptor signaling pathway, were involved in Klebsiella pneumoniae pulmonary infection. Using ICEPOP (Immune CEll POPulation) analysis, we found that several cell types were involved in the host immune response to Klebsiella pneumoniae pulmonary infection, including dendritic cells, macrophages, monocytes, NK (natural killer) cells, stromal cells. Further, IL-17 chemokines were significantly increased during Klebsiella pneumoniae infection. This study provided evidence for further studying the pathogenic mechanism of Klebsiella pneumoniae pneumonia infection.