The Role of Bacteria-derived Outer-Membrane-Vesicles (OMVs) in the Induction of Systemic Inflammation and Organ Damage

通过血管内皮细胞调节血管通透性和白细胞迁移是全身炎症发病机制中的一个重要过程。这些过程的失调可能通过造成组织水肿形成和细胞介导的器官组织破坏而导致广泛的损害。目前的研究表明，细菌外膜囊泡(OMV)在全身性炎症中具有极其重要的作用，特别是在肺炎和败血症等临床疾病中，这些疾病是世界范围内导致死亡的主要原因之一。为了研究OMV在全身炎症过程中与血管内皮细胞和免疫细胞相互作用时作为生物标志物和治疗靶点的巨大潜力，本项目将通过实验室研究和临床观察试验来解决这些新的方面。根据初步结果，假设革兰氏阴性菌(如大肠杆菌和肺炎克雷伯菌)的OMV在感染过程中诱导全身炎症、血管内凝血和肺/器官损伤方面发挥主要作用。这些知识将对开发控制这些疾病的新战略至关重要，对于开发OMV作为早期诊断工具的潜力也很重要。该项目将表征不同临床相关细菌株(如大肠杆菌和肺炎克雷伯菌)在体内和体外不同炎症条件下分离的OMV的释放和组成。OMVS在复杂生物系统中的病理生理学作用将在不同的小鼠体内炎症性疾病模型中进行研究，例如细菌性肺炎。这也将得到最先进的活体成像技术的补充，例如肺活体显微镜。

The regulation of vascular permeability and leukocyte transmigration through vascular endothelial cells is a crucial process in the pathogenesis of systemic inflammatory conditions. Dysregulation of these processes may induce extensive damage by inflicting tissue oedema formation and cell-mediated destruction of organ tissue. Current research has shown the tremendous importance of bacterial outer membrane vesicles (OMVs) in systemic inflammation, particularly in pneumonia and sepsis, clinical maladies which are among the leading causes of mortality world-wide. To investigate the tremendous potential of OMVs as a biomarker and therapeutic target during their interaction with the vascular endothelium and immune cells during systemic inflammation, this project will address these novel aspects by laboratory investigations and clinical observational trials. Based on preliminary results, the hypothesis ist that OMVs of Gram-negative bacteria (such as E. coli and K. pneumoniae) play a major role in the induction of systemic inflammation, intravascular coagulation, and lung/organ damage during the infection. This knowledge will be vital for the development of novel strategies to control these diseases and important to exploit the potential of OMVs as a tool for early-stage diagnostics. This project will characterize the release and composition of OMVs isolated by different clinically relevant bacterial strains, e.g., E. coli and K. pneumoniae, under different inflammatory conditions in vivo and in vitro. The pathophysiological role of OMVs in complex biological systems will be investigated in different murine in vivo models of inflammatory diseases, e.g., bacterial pneumonia. This will also be complemented by state-of-the-art intravital imaging techniques, e.g., lung intravital microscopy.