Comparison of Sepsis-Induced Transcriptomic Changes in a Murine Model to Clinical Blood Samples Identifies Common Response Patterns

Abstract

Experimental models, mimicking physiology, and molecular dynamics of diseases in human, harbor the possibility to study the effect of interventions and transfer results from bench to bedside. Recent advances in high-throughput technologies, standardized protocols, and integration of knowledge from databases yielded rising consistency and usability of results for inter-species comparisons. Here, we explored similarities and dissimilarities in gene expression from blood samples of a murine sepsis model (peritoneal contamination and infection, PCI) and patients from the pediatric intensive care unit (PICU) measured by microarrays. Applying a consistent pre-processing and analysis workflow, differentially expressed genes (DEG) from PCI and PICU data significantly overlapped. A major fraction of DEG was commonly expressed and mapped to adaptive and innate immune response related pathways, whereas the minor fraction, including the chemokine (C–C motif) ligand 4, exhibited constant inter-species disparities. Reproducibility of transcriptomic observations was validated experimentally in PCI. These data underline, that inter-species comparison can obtain commonly expressed transcriptomic features despite missing homologs and different protocols. Our findings point toward a high suitability of an animal sepsis model and further experimental efforts in order to transfer results from animal experiments to the bedside.

Immunosuppression after Sepsis: Systemic Inflammation and Sepsis Induce a Loss of Naïve T-Cells but No Enduring Cell-Autonomous Defects in T-Cell Function

“…Lipopolysaccharide or unmethylated CpG oligonucleotides act via the pattern recognition receptors TLR4 or TLR9, respectively, to elicit a pronounced systemic inflammation characterised by the rapid surge of pro-inflammatory mediators in serum [49] , [50] . These two models of SIRS were compared with the effects of polymicrobial septic peritonitis induced by the intraperitoneal injection of a microbiologically characterised and calibrated suspension of human faeces (referred to as PCI, for p eritoneal c ontamination and i nfection [46] , [51] , [52] ) or, alternatively, by cecal ligation and puncture (CLP). LPS and septic peritonitis induced pronounced sickness with lethargy, weight loss, weakness and general morbidity along with high dose-dependent mortality rates ( Fig.…”

An integrated transcriptome and expressed variant analysis of sepsis survival and death

“…Likewise, great efforts have been made to identify host factors associated with sepsis recovery versus death. In recent years, tools have become available to explore these questions comprehensively including gene expression analysis [ 50 - 53 ], metabolomics [ 11 , 54 , 55 ], proteomics [ 11 , 56 - 58 ], microRNA analysis [ 59 - 61 ], as well as the integration of these multi-omic approaches with comprehensive clinical features [ 11 ]. In contrast to previous work, this study utilized mRNA sequencing, rather than microarrays, to characterize the transcriptome.…”

New Approaches to Treat Sepsis: Animal Models «Do Not Work» (Review)

“…When comparing experimental young mice with young human patients in clinical situations, there were still differences. For instance, a transcriptome analysis revealed 131 genes modulated by sepsis which were identified as common ones for mice and children versus 486 genes specific for children and 593 genes specific for mice [27].…”

“…При сравнении экспериментальных молодых мышей с молодыми пациентами в клинических ситуациях, различия все равно будут присутствовать. Так, транскриптомный анализ выявил 131 ген, модулированный сепсисом, которые были идентифицированы, как общие для мышей и детей, против 486 специфичных для детей и 593 специфичных для мышей [27].…”