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Markers and scores for sepsis

Human Endogenous Retroviruses as markers of severity in Sepsis

April 20 • P3053

M. Mommert1, O. Tabone2, K. Brengel-Pesce1, E. Cerrato2, V. Cheynet1, M. Denizot2, P. Fournier1, A. Guichard1/2, M. Naville3, G. Oriol1, A. Pachot2, A. Lepape4, G. Monneret2/5, F. Venet2/5, JN. Volff3, J. Textoris2/6, F. Mallet1/2

1) Joint research unit Hospices Civils de Lyon - bioMérieux, Centre Hospitalier Lyon Sud, 165 Chemin du Grand Revoyet, 69310 Pierre-Bénite, France
2) EA 7426 Pathophysiology of Injury-Induced Immunosuppression, Université Claude Bernard Lyon 1 - Hospices Civils de Lyon - bioMérieux, Joint Research Unit HCL-bioMérieux, Immunology Laboratory & Anesthesia and Critical Care Medicine Department, Edouard Herriot Hospital, Lyon, France
3) Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, CNRS UMR 5242, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, 46 allée d'Italie F-69364 Lyon, France
4) Hospices Civils de Lyon, Intensive Care Unit, Centre Hospitalier Lyon Sud, 165 Chemin du Grand Revoyet, 69310 Pierre-Bénite, France
5) Hospices Civils de Lyon, Immunology Laboratory, Hôpital Edouard Herriot, 5 Place d’Arsonval, 69437 Lyon Cedex 3, France
6) Hospices Civils de Lyon, Department of Anaesthesiology and Critical Care Medicine, Hôpital Edouard Herriot, 5 Place d’Arsonval, 69437 Lyon Cedex 3, France

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.



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