Transcriptional characterization of sepsis in a LPS porcine model

Abstract

This paper identifies gene candidates differentially expressed in the porcine brain during sepsis, designed for eventual application in human clinical care for earlier detection of sepsis, as no known biomarkers currently exist. Sepsis associated encephalopathy (SAE) is characterized by dysregulated molecular pathways of the immune response impinging upon normal central nervous system (CNS) function and ultimately resulting in lasting cognitive and behavioral impairments. This study seeks to identify gene candidates that exhibit altered transcriptional expression during sepsis. Twelve Yorkshire pigs (n = 6 for saline control and lipopolysaccharide group) were utilized. LPS injection rate was 0.5-0.75 mL/kg resulting in death within 5-10 h. Brain tissue was collected and analyzed via bulk RNA-seq, and corresponding computational genomic analysis. Multiple genes demonstrated significant differential expression in the early septic brain, correlating with endothelial cell disruption, immune/inflammatory alterations, and potential alterations in microglia. Gene candidates downregulated include: OCLN, SLC19A3, and SLC52A3. Genes upregulated include: ICAM1, IRF1, CXCL10, and ZFP36. Specific gene candidates were identified as early changes in the septic brain that could be targets to prevent long-term cognitive and behavioral changes seen in sepsis survivors and establish a baseline diagnostic panel to interrogate in animal models with the goal of advancing treatments for human patients who experience sepsis.

Keywords: Computational genomics; Neurodegeneration; Neuroinflammation; Pig model; RNA sequencing; Sepsis.