Background: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The heterogeneity of the disease presents a major clinical challenge with regard to therapeutic coverage, and to this day the proposed markers are not enough to stratify patients. The human endogenous retroviruses (HERVs) could be relevant markers, due to their expression in inflammatory and autoimmune diseases and their emerging immunological properties (envelopes and non-coding sequences).
Materials/methods: In order to determine to what extent the HERVs are expressed and modulated in the blood compartment, in inflammatory and immunocompromised contexts in vitro and in vivo, we used a custom high density DNA chip allowing the transcription analysis of 360 689 HERVs. The HERVs expression was objectified in endotoxin tolerance (ET) ex vivo model in peripheral blood mononuclear cells (PBMCs) of healthy volunteers and in whole blood of healthy volunteers and 120 septic shock patients, stratified or not according to the immune status determined by mHLA-DR level.
Results: About 7% of HERVs are expressed in the blood compartment including notably hundreds of identified HERV-H and PRIMA-41 loci. The HERV transcriptome is modulated in ex vivo ET model, letting appear two major transcriptional phenotypes. Major differences in HERVs expression was observed between septic patients and healthy volunteers. More, the HERVs transcriptome was modulated between septic patients, according to their immune status. Using a signature of modulated elements, we have been able to stratify an independent validation cohort with a clear difference in severity between two clusters of patients.
Conclusions: We illustrated the importance of addressing both the exome and repetitive DNA repertoires to increase our understanding of sepsis pathophysiology. The added value of these newly identified HERVs markers should be evaluated in a larger cohort of septic patients. If they prove to be robust, they could further serve as a stratification tool prior to immunostimulatory treatment and to monitor drug efficacy, which could contribute to the reduction of mortality in sepsis patients.