基于单细胞测序的肺炎相关性脓毒症免疫细胞调节性死亡机制研究

肺炎相关性脓毒症（pneumonia-derived sepsis）是肺炎的主要致死性并发症，它以感染后宿主全身炎症反应失调和免疫紊乱为特征。研究显示，除凋亡外尚有多种调节性细胞死亡（RCD）机制参与脓毒症免疫细胞死亡，使宿主处于免疫紊乱状态，导致高死亡率。治疗脓毒症的最有效策略可能是针对不同RCD方式给予联合治疗。我们前期研究发现，在肺炎早期尚未发生脓毒症时，机体已发生显著免疫紊乱，并与预后相关。因此，何时干预也有争议。目前在肺炎相关性脓毒症病理进程中，不同免疫细胞的死亡调控方式及其触发因素仍待明确。本研究拟通过肺炎相关性脓毒症小鼠模型，模拟肺部细菌负荷逐渐增加，并发多器官损害和脓毒症的真实过程；基于单细胞高通量RNA测序，寻找病理状态下免疫细胞群死亡调控方式改变及核心驱动基因；同时探索宿主免疫状态改变的关键时间节点；为今后临床探索联合治疗策略，以及寻找实施干预措施的最佳治疗窗提供思路。

Pneumonia is a significant burden on the public health and economic stability of societies all over the world. The threat posed by pneumonia is further deepened by the emerging contagious diseases and the increased incidence of drug-resistant pathogen variants. The efficient management of its fatal complications like sepsis would improve the outcome. Pneumonia-derived sepsis is defined as a dysregulated systemic inflammatory response to pneumonia and is associated with immune dysfunction and acute organ dysfunction. Recent studies indicate that in addition to apoptosis, a variety of regulated cell death (RCD) mechanisms are involved in sepsis-induced immune dysfunction. The most promising therapeutic strategy for sepsis might be a combination of therapies targeting different RCD mechanisms. Also, the optimizing timing of a therapeutic intervention remains unclear. In a pilot study, we found that the host immune dysregulation happened in the early stage of pneumonia, far before sepsis. Besides, the immune dysregulation was significantly associated with clinical outcome. To date, the details of immune cell death regulation, and trigger factors are not precise in the occurrence and development of pneumonia-derived sepsis. We here aim to determine the underlying mechanisms of immune cell death regulation during pneumonia-derived sepsis using high-throughput single-cell RNA sequencing. The application of a mice model of pneumonia and sepsis would allow us to follow the clinical scenario of a gradually growing bacterial load in the lungs with subsequent dissemination to distant body sites resulting in sepsis. The timing of the host immune function alternations in regards to pneumonia and sepsis would also be explored. The study would be useful in the further therapeutic exploration of possible combined therapies and optimal intervention time.