Single-cell profiling reveals a conserved role for hypoxia-inducible factor signaling during human craniotomy infection. Van Roy, et al.

Neurosurgeries complicated by infection are associated with prolonged treatment and significant morbidity. Craniotomy is a common neurosurgical procedure; however, the cellular and molecular signatures associated with craniotomy infection in human subjects are unknown. A retrospective study of over 2,500 craniotomies reveals diverse patient demographics, pathogen identity, and surgical landscapes associated with infection. Leukocyte profiling in tissues from craniotomy infection patients characterizes a predominance of granulocytic myeloid-derived suppressor cells that may arise from transmigrated blood neutrophils, based on scRNA-seq trajectory analysis. Single-cell transcriptomic analysis identifies metabolic shifts in tissue leukocytes, including a conserved hypoxia-inducible factor (HIF) signature. The importance of HIF signaling was validated using a mouse model of Staphylococcus aureus craniotomy infection, where HIF inhibition increases chemokine production and leukocyte recruitment, exacerbating tissue pathology. These findings establish conserved metabolic and transcriptional signatures that may represent promising future therapeutic targets for human craniotomy infection in the face of increasing antimicrobial resistance.

感染并发症的神经外科手术与治疗延长及显著的发病率相关。颅骨切开术是一种常见的神经外科程序；然而，与人类受试者颅骨切开术感染相关的细胞和分子特征尚不清楚。一项对超过2,500例颅骨切开术的回顾性研究揭示了与感染相关的多样化患者人口统计学、病原体身份和手术场景。通过对颅骨切开术感染患者组织中的白细胞进行白细胞谱分析，发现以粒细胞来源的髓源性抑制细胞为主，这些细胞可能源自迁移的血中性粒细胞，这是基于单细胞RNA测序轨迹分析得出的。单细胞转录组分析识别了组织白细胞中的代谢转变，包括一个保守的缺氧诱导因子（HIF）特征。通过使用金黄色葡萄球菌颅骨切开术感染小鼠模型验证了HIF信号通路的重要性，其中HIF抑制增加了趋化因子产生和白细胞募集，加剧了组织病理学。这些发现确立了保守的代谢和转录特征，这些特征可能代表针对人类颅骨切开术感染在日益增长的抗菌素耐药性面前的潜在未来治疗靶点。