Characterizing the Role of Pre-Pubertal Status in Sepsis: Why Do Children Survive When Adults Do Not

Abstract

Epidemiological data from both historical and contemporary sources suggest that pre-pubertal children possess a relative resistance to death from severe infections and sepsis. To assess the role that pubertal status may play in protection from sepsis mortality, we employed two different experimental strategies. In our first strategy, we demonstrated the significant enhancement of survival in pre-pubertal animals using an experimental mouse model of endotoxemia. Although both pre- and post-pubertal animals exhibited an equally robust initial response to endotoxin, there were significant age-associated differences in cytokine and leukocyte dynamics later on. Prevention or acceleration of puberty by hormonal manipulation resulted in increased or decreased survival respectively, highlighting the importance of the pubertal transition in defining the resistance phenotype. In addition, the adoptive transfer of pre-, but not post-pubertal, peritoneal cells improved the survival of post-pubertal recipient mice, supporting our hypothesis that a pre-pubertal biology may hold the key to improving the survival of adults. In our second strategy, we sought to identify drug candidates for the treatment of sepsis by data-mining publicly available whole blood transcriptomes from septic adults and children. Pathprint, a pathways-based transcriptome analysis platform, was used to highlight key differences between the two age groups. Subsequently, a novel in-silico drug development system was used to identify agents that might promote beneficial pathways (i.e. activated in children) or inhibit harmful ones (i.e. activated in adults). This method uses a pathway-drug network (PDN) to probe specific clusters of pathways exhibiting age-associated differences for correlations with drug-based gene signatures built into the network. We validated resultant drug candidates by literature curation, and found that the PDN method produced a substantially higher rate of positives when compared to a purely gene-level ConnectivityMap analysis. Additionally, in direct testing using an endotoxemia model of murine sepsis, 5 of 10 compounds tested significantly improved survival.