Acinetobacter baumannii inhibits the PLK2/FoxO axis to induce oxidative stress and cell barrier dysfunction

Acinetobacter baumannii is a clinically prevalent opportunistic Gram-negative pathogen. Currently, hypervirulent A. baumannii strains have spread worldwide, while their molecular pathogenic mechanisms and effective therapeutic agents remain incompletely understood. This study aims to elucidate the core molecular mechanisms driving the pathogenesis of hypervirulent A. baumannii. Using transcriptomic profiling, we identified differentially expressed genes (DEGs) in human bronchial epithelial cells (BEAS-2B) infected with hypervirulent A. baumannii. In in vitro experiments, infection models were established using both BEAS-2B and HBE cell lines. The alterations in the PLK2 and FoxO signaling pathways were detected via western blot, qRT-PCR, and immunofluorescence assays. Intracellular oxidative stress levels were measured using dichlorodihydrofluorescein diacetate (DCFH-DA) probes. Transcriptomic analyses identified PLK2 as a key DEG, and the FoxO-mediated oxidative stress pathway was determined to be a key differentially regulated pathway after being infected by A. baumannii. Compared with the control group, the expression levels of PLK2, FoxO1, and FoxO3a were downregulated, intracellular ROS production was elevated, and the expression levels of barrier function-related proteins including ZO-1, Occludin, and E-cadherin were disrupted in the infection group. Inhibition or activation of PLK2 could, respectively, exacerbate and alleviate cell damage. In summary, this study reveals the effect of hypervirulent A. baumannii infection on PLK2 in host cells. It provides a new perspective for understanding the pathogenic mechanisms of hypervirulent A. baumannii and establishes an important theoretical basis for developing targeted therapeutic strategies in clinical practice. PLK2 may serve as a promising novel therapeutic target for hypervirulent A. baumannii infections.IMPORTANCEThis study provides crucial insights into the molecular pathogenesis of hypervirulent A. baumannii (HV A. b), a widespread and clinically challenging opportunistic pathogen. By establishing infection models in human bronchial epithelial cells (BEAS-2B and HBE) and performing transcriptomic analysis, the present study identified Polo-like kinase 2 (PLK2) as the most significantly dysregulated gene upon HV A. b infection. Furthermore, it revealed the critical involvement of the Forkhead box O (FoxO) signaling pathway and excessive intracellular oxidative stress in mediating bacterial pathogenesis. Key experimental findings demonstrate that HV A. b strains significantly suppress the protein levels of PLK2, FoxO1, and FoxO3a, thereby triggering intracellular ROS accumulation and impairing epithelial barrier function. The pivotal regulatory role of PLK2 uncovered in this work offers new perspective for understanding HV A. b virulence mechanisms. Importantly, this study identifies PLK2 as a highly promising novel therapeutic target for developing urgently needed targeted strategies against these difficult-to-treat infections.