Gene expression profiling in sepsis: timing, tissue, and translational considerations

Abstract

Sepsis is a complex inflammatory response to infection. Microarray-based gene expression studies of sepsis have illuminated the complex pathogen recognition and inflammatory signaling pathways that characterize sepsis. More recently, gene expression profiling has been used to identify diagnostic and prognostic gene signatures, as well as novel therapeutic targets. Studies in pediatric cohorts suggest that transcriptionally distinct subclasses may account for some of the heterogeneity seen in sepsis. Time series analyses have pointed to rapid and dynamic shifts in transcription patterns associated with various phases of sepsis. These findings highlight current challenges in sepsis knowledge translation, including the need to adapt complex and time-consuming whole-genome methods for use in the intensive care unit environment, where rapid diagnosis and treatment are essential.

Shared and Distinct Aspects of the Sepsis Transcriptomic Response to Fecal Peritonitis and Pneumonia

“…Additionally, the extent to which the source of infection contributes to heterogeneity in the transcriptomic response is unclear, although there is evidence that gene expression signatures can distinguish between gram-positive, gramnegative, and viral etiologies, and these signatures may be useful in the diagnosis of CAP (6)(7)(8)(9)(10)(11)(12)(13). In fecal peritonitis (FP), sepsis is triggered by a polymicrobial infection within the peritoneal cavity, complicated by the release of damage-associated molecular patterns (DAMPs) and the effects of anesthesia (14).…”

Postnatal Age Is a Critical Determinant of the Neonatal Host Response to Sepsis

“…Expression measurement of the entire genome would not be required once a suitable set of predictive genes (<100) is identified. The identification of molecular endotypes that identify classes of infants via modern multiplex messenger RNA (mRNA) quantification platforms can be obtained rapidly (8)(9)(10)(11)(12) h) (38,39). Integration of these techniques into intensive care environments has great potential to benefit patient populations with diverse clinical presentations of infection such as preterm neonates.…”

“…Lastly, the use of multiple definitions for sepsis in neonates severely limits the ability to build on experimental findings between research groups and hinders progress toward an improved understanding of the pathophysiology (9). Molecular endotyping can be successfully leveraged to identify diagnostic and prognostic gene signatures, identify novel therapeutic targets, uncover mechanisms behind differential sepsis outcomes, and reveal rapid and dynamic shifts in transcription patterns associated with various phases of sepsis (10). We and others have shown genome-wide expression profiling (GWEP) can be a powerful tool to help uncover sepsis pathophysiology and reveal unique molecular endotypes among pediatric patients (11)(12)(13)(14)(15).…”

Septic Shock in Older People

“…In the course of sepsis, transition of the inlammatory response to standard immunosuppression has been suggested to explain the disappointing results obtained by clinical studies that investigated the use of anti-inlammatory drugs in this population of patients [39][40][41]. Transcriptomic analysis on a large scale has provided interesting information in this regard, showing that speciic groups of patients actually have singular proiles [42][43][44]. However, a recently published systematic review was unable to detect distinct pro-inlammatory and anti-inlammatory phases in sepsis or diferences in gene expression when analyzing diferent sub-populations [45].…”