College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
Front Cell Infect Microbiol. 2022 Apr 27;12:833080. doi: 10.3389/fcimb.2022.833080. eCollection 2022.
Hypervirulent (hvKp) can cause life-threatening community-acquired infections among healthy young individuals and is thus of concern for global dissemination. In this study, a mouse model of acute primary hvKp pneumonia was established aerosolized intratracheal (i.t.) inoculation, laying the foundation for conducting extensive studies related to hvKp. Subsequently, a time-course transcriptional profile was created of the lungs from the mouse model at 0, 12, 24, 48 and 60 hours post-infection (hpi) using RNA Sequencing (RNA-Seq). RNA-Seq data were analyzed with the use of Mfuzz time clustering, weighted gene co-expression network analysis (WGCNA) and Immune Cell Abundance Identifier for mouse (ImmuCellAI-mouse). A gradual change in the transcriptional profile of the lungs was observed that reflected expected disease progression. At 12 hpi, genes related to acute phase inflammatory response increased in expression and lipid metabolism appeared to have a pro-inflammatory effect. At 24 hpi, exacerbation of inflammation was observed and active IFN-γ suggested that signaling promoted activation and recruitment of macrophages occurred. Genes related to maintaining the structural integrity of lung tissues showed a sustained decrease in expression after infection and the decrease was especially marked at 48 hpi. TNF, IL-17, MAPK and NF-kB signaling pathways may play key roles in the immunopathogenesis mechanism at all stages of infection. Natural killer (NK) cells consistently decreased in abundance after infection, which has rarely been reported in hvKp infection and could provide a new target for treatment. Genes and were significantly upregulated during infection. Both , which is associated with lipopolysaccharide (LPS) that elicits host inflammatory response, and , which encodes an antimicrobial protein, have not previously been reported in hvKp infections and could be important targets for subsequent studies. To t our knowledge, this paper represents the first study to investigate the pulmonary transcriptional response to hvKp infection. The results provide new insights into the molecular mechanisms underlying the pathogenesis of hvKp pulmonary infection that can contribute to the development of therapies to reduce hvKp pneumonia.
高毒力（hvKp）能够导致健康的年轻个体发生危及生命的社区获得性感染，因此受到全球关注。在本研究中，通过气溶胶气管内（i.t.）接种建立了急性原发性 hvKp 肺炎小鼠模型，为开展与 hvKp 相关的广泛研究奠定了基础。随后，使用 RNA 测序（RNA-Seq）对感染后 0、12、24、48 和 60 小时的小鼠模型肺部进行了时间过程转录谱分析。使用 Mfuzz 时间聚类、加权基因共表达网络分析（WGCNA）和用于小鼠的免疫细胞丰度鉴定（ImmuCellAI-mouse）对 RNA-Seq 数据进行了分析。观察到肺部转录谱的逐渐变化，反映了预期的疾病进展。在 12 hpi 时，与急性炎症反应相关的基因表达增加，脂质代谢似乎具有促炎作用。在 24 hpi 时，观察到炎症加剧，活跃的 IFN-γ表明信号促进了巨噬细胞的激活和募集。感染后，与维持肺组织结构完整性相关的基因表达持续下降，尤其是在 48 hpi 时。TNF、IL-17、MAPK 和 NF-kB 信号通路可能在感染的所有阶段的免疫发病机制中发挥关键作用。感染后自然杀伤（NK）细胞的丰度持续下降，这在 hvKp 感染中很少报道，可能为治疗提供新的靶点。在感染过程中，基因 和 显著上调。两者均与引发宿主炎症反应的脂多糖（LPS）相关，而 编码一种抗菌蛋白，以前在 hvKp 感染中未报道过，可能是后续研究的重要靶点。据我们所知，本文代表了第一项研究 hvKp 感染后肺部转录反应的研究。研究结果为 hvKp 肺部感染发病机制的分子机制提供了新的见解，有助于开发减少 hvKp 肺炎的疗法。
