Unraveling the mechanism of sepsis-mediated multiple organ dysfunction syndrome by RNA sequencing analysis in the pediatric population

Abstract

Abstract Sepsis is a significant healthcare burden, with high morbidities and mortalities and no specific therapy is yet available. More than 42,000 children develop severe sepsis each year in the U.S and 67% of those patients develop multiple organ dysfunction syndrome (MODS). In this study we aim to elucidate the mechanism of sepsis-mediated MODS by RNAseq analysis in PBMCs from the peripheral blood of pediatric patients. Comparison between control and septic patients revealed that transcriptomic signatures associated with receptor-mediated endocytosis (Iglc3, Igkv3d-20), anaphase-promoting complex (APC)-dependent catabolic process (Pttg1, Cdc20) heme-metabolism (Alas2, Slc25a39) and oxygen transport (hemoglobulin pathway) (Hbb, Hba2, Hbq1) were upregulated in sepsis. Heme/hemoglobulin related genes were downregulated in the recovery phase of those patients. In addition, neutrophil chemotaxis (CCL3L1, IL1B, CCL4L2, CCL3), phagocytosis (IGLL5, IGHG1, IGHG2), and interleukin-1 receptor binding (IL1RN, IL1B) pathways were upregulated in the recovery phase, while T cell activation (CD2, ITK, ZAP70, CD8A, TREML2) and differentiation (LCK, IL7R), and negative regulation of NIK/NF-kappaB signaling (SPAN6, CPNE1, ADIPOR1) pathways were downregulated. Many of those genes upregulated in the septic patients are associated with lower survival probability in the adult population, while genes upregulated in the recovery phase are associated with higher survival probability, based on the Biological Information Database of Sepsis (BIDOS). Given data on the pediatric population are scarce, our study reveals unique gene signatures of PBMCs associated with pediatric sepsis that could be novel targets for therapeutic intervention. Supported by R21HD099194-01A1, NICHD The Anesthesia Research Distinguished Trailblazer Award, Boston Children's Hospital