Single-Cell transcriptomic profiles of peripheral blood immune cells reveal early monocyte and platelet activation in the transition from high-risk states to clinical sepsis.

Sepsis, due to dysregulated host responses to infection, demands early intervention. Nevertheless, it is challenging to identify immune changes in the transition from high-risk states to sepsis, which remains unclear. Here, we profiled the single-cell transcriptome of peripheral blood immune cells in healthy controls, high-risk individuals, and clinical sepsis patients to characterize the transcriptomic reprogramming featured by the monocyte and platelet activation across sepsis progression. Particularly, a core gene set (S100A8, S100A9, IFITM2, IFITM3) showed significant upregulation in monocytes in both the high-risk stage and clinical sepsis. Moreover, platelets also exhibited early activation of coagulation and inflammatory pathways, notably sharing this core gene set upregulation. We further analyzed Single-cell RNA Sequencing (scRNA-seq) data from independent cohorts of very preterm infants with sepsis and elderly patients with diabetes. The consistent, early, and persistent upregulation of the S100A8/A9 and IFITM2/3 monocyte signature was strikingly observed across these diverse, high-risk populations. This study provides novel single-cell insights into immune dysregulation during sepsis onset, pinpointing specific transcriptomic signatures in monocytes and platelets emerging during the high-risk phase.