Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.
Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.
Front Immunol. 2023 Sep 26;14:1257834. doi: 10.3389/fimmu.2023.1257834. eCollection 2023.
COVID-19 and sepsis represent formidable public health challenges, characterized by incompletely elucidated molecular mechanisms. Elucidating the interplay between COVID-19 and sepsis, particularly in geriatric patients suffering from sepsis-induced acute respiratory distress syndrome (ARDS), is of paramount importance for identifying potential therapeutic interventions to mitigate hospitalization and mortality risks.
We employed bioinformatics and systems biology approaches to identify hub genes, shared pathways, molecular biomarkers, and candidate therapeutics for managing sepsis and sepsis-induced ARDS in the context of COVID-19 infection, as well as co-existing or sequentially occurring infections. We corroborated these hub genes utilizing murine sepsis-ARDS models and blood samples derived from geriatric patients afflicted by sepsis-induced ARDS.
Our investigation revealed 189 differentially expressed genes (DEGs) shared among COVID-19 and sepsis datasets. We constructed a protein-protein interaction network, unearthing pivotal hub genes and modules. Notably, nine hub genes displayed significant alterations and correlations with critical inflammatory mediators of pulmonary injury in murine septic lungs. Simultaneously, 12 displayed significant changes and correlations with a neutrophil-recruiting chemokine in geriatric patients with sepsis-induced ARDS. Of these, six hub genes (CD247, CD2, CD40LG, KLRB1, LCN2, RETN) showed significant alterations across COVID-19, sepsis, and geriatric sepsis-induced ARDS. Our single-cell RNA sequencing analysis of hub genes across diverse immune cell types furnished insights into disease pathogenesis. Functional analysis underscored the interconnection between sepsis/sepsis-ARDS and COVID-19, enabling us to pinpoint potential therapeutic targets, transcription factor-gene interactions, DEG-microRNA co-regulatory networks, and prospective drug and chemical compound interactions involving hub genes.
Our investigation offers potential therapeutic targets/biomarkers, sheds light on the immune response in geriatric patients with sepsis-induced ARDS, emphasizes the association between sepsis/sepsis-ARDS and COVID-19, and proposes prospective alternative pathways for targeted therapeutic interventions.
COVID-19 和脓毒症是严峻的公共卫生挑战，其分子机制尚不完全清楚。阐明 COVID-19 与脓毒症之间的相互作用，特别是在患有脓毒症诱导的急性呼吸窘迫综合征（ARDS）的老年患者中，对于确定潜在的治疗干预措施以降低住院和死亡风险至关重要。
我们采用生物信息学和系统生物学方法，鉴定了 COVID-19 感染以及合并或相继发生感染时，管理脓毒症和脓毒症诱导的 ARDS 的枢纽基因、共享途径、分子生物标志物和候选治疗药物。我们利用脓毒症-ARDS 小鼠模型和老年脓毒症诱导的 ARDS 患者的血液样本验证了这些枢纽基因。
我们的研究发现了 COVID-19 和脓毒症数据集之间共有的 189 个差异表达基因（DEGs）。我们构建了一个蛋白质-蛋白质相互作用网络，揭示了关键的枢纽基因和模块。值得注意的是，9 个枢纽基因在脓毒症小鼠肺部的关键炎症介质与肺损伤中显示出显著的改变和相关性。同时，12 个枢纽基因在老年脓毒症诱导的 ARDS 患者中与招募中性粒细胞的趋化因子显示出显著的变化和相关性。其中，6 个枢纽基因（CD247、CD2、CD40LG、KLRB1、LCN2、RETN）在 COVID-19、脓毒症和老年脓毒症诱导的 ARDS 中均有显著改变。我们对不同免疫细胞类型的枢纽基因进行单细胞 RNA 测序分析，为疾病发病机制提供了深入了解。功能分析强调了脓毒症/脓毒症-ARDS 和 COVID-19 之间的相互联系，使我们能够确定潜在的治疗靶点、转录因子-基因相互作用、DEG- microRNA 共调控网络以及涉及枢纽基因的潜在药物和化学化合物相互作用。
我们的研究提供了潜在的治疗靶点/生物标志物，阐明了老年脓毒症诱导的 ARDS 患者的免疫反应，强调了脓毒症/脓毒症-ARDS 和 COVID-19 之间的关联，并提出了针对潜在治疗干预的替代途径。
