Multi-modal single-cell sequencing of circulating mononuclear cells deconvolutes outcome-specific immune responses in trauma patients

Immune dysfunction plays a key role in contributing to high morbidity and mortality after trauma. To identify the immune cell subsets associated with a specific clinical trajectory (SR vs. FR, slow vs. fast recovery), we isolated the peripheral blood mononuclear cells from 16 trauma patients, including 8 SR patients (ICU days > 7) and 8 FR patients (ICU days < 7) at 72 hours after injury, along with 4 age and sex matched healthy controls. A total of 20 samples were subjected to DOGMA-seq, a tri-modal single-cell assay that measures gene expression, open chromatin accessibility, and surface protein expression simultaneously in the same cells. Integrated analysis revealed patient group-specific changes in T cells and monocytes. SR patients had lower numbers of cytotoxic T cells (CTLs) and these remaining CTLs were less cytotoxic. We identified a subset of monocytes overrepresented in FR patients. We extracted the genes specifically upregulated in this subset and queried a published whole blood transcriptome dataset of 167 trauma patients. These genes were positively correlated with T cell activation pathways, and were also correlated with a quicker recovery in this bulk dataset. Thus, we were able to validate our findings derived from DOGMA-seq from 16 trauma patients in a much larger cohort. Our analysis provides a landscape of immune responses in trauma patients based on clinical trajectories and characterizes the outcome-specific changes across cell types.