Dynamic changes in human single-cell transcriptional signatures during fatal sepsis

Abstract

Abstract Systemic infections, especially in patients with chronic diseases, may result in sepsis: an explosive immune response that can lead to multisystem organ failure with a high mortality rate. Patients with similar clinical phenotypes or sepsis biomarker expression upon diagnosis may have different outcomes, suggesting that the dynamics of sepsis is critical in disease progression. A within-subject study of patients with Gram-negative bacterial sepsis with surviving and fatal outcomes was designed and single-cell transcriptomic analyses of peripheral blood mononuclear cells (PBMC) collected during the critical period between sepsis diagnosis and 6 h were performed. The single-cell observations in the study are consistent with trends from public datasets but also identify dynamic effects in individual cell subsets that change within hours. It is shown that platelet and erythroid precursor responses are drivers of fatal sepsis, with transcriptional signatures that are shared with severe COVID-19 disease. It is also shown that hypoxic stress is a driving factor in immune and metabolic dysfunction of monocytes and erythroid precursors. Last, the data support CD52 as a prognostic biomarker and therapeutic target for sepsis as its expression dynamically increases in lymphocytes and correlates with improved sepsis outcomes. In conclusion, this study describes the first single-cell study that analyzed short-term temporal changes in the immune cell populations and their characteristics in surviving or fatal sepsis. Tracking temporal expression changes in specific cell types could lead to more accurate predictions of sepsis outcomes and identify molecular biomarkers and pathways that could be therapeutically controlled. This research was supported by the UCR School of Medicine (to A.G. and M.G.N.), the Dean Innovation Fund (to J.B. and M.G.N.), and the National Institutes of Health (NIAID, R21AI37830, and R01AI153195 to M.G.N.). The data from this study were generated at the UC San Diego IGM Genomics Center utilizing an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).