Dynamic LTR retrotransposon transcriptome landscape in septic shock patients

Abstract

Background: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Numerous studies have explored the complex and dynamic transcriptome modulations observed in sepsis patients, but a large fraction of the transcriptome remains unexplored. This fraction could provide information to better understand sepsis pathophysiology. Multiple levels of interaction between human endogenous retroviruses (HERV) and the immune response have led us to hypothesize that sepsis is associated with HERV transcription and that HERVs may contribute to a signature among septic patients allowing stratification and personalized management. Methods: We used a high-density microarray and RT-qPCR to evaluate the HERV and Mammalian Apparent Long Terminal Repeat retrotransposons (MaLR) transcriptome in a pilot study that included 20 selected septic shock patients, stratified on mHLA-DR expression, with samples collected on day 1 and day 3 after inclusion. We validated the results in an unselected, independent cohort that included 100 septic shock patients on day 3 after inclusion. We compared septic shock patients, according to their immune status, to describe the transcriptional HERV/MaLR and conventional gene expression. For differential expression analyses, moderated t tests were performed and Wilcoxon signed-rank tests were used to analyze RT-qPCR results. Results: We showed that 6.9% of the HERV/MaLR repertoire was transcribed in the whole blood, and septic shock was associated with an early modulation of a few thousand of these loci, in comparison to healthy volunteers. We provided evidence that a subset of HERV/MaLR and conventional genes were differentially expressed in septic shock patients, according to their immune status, using monocyte HLA-DR (mHLA-DR) expression as a proxy. A group of 193 differentially expressed HERV/MaLR probesets, tested in an independent septic shock cohort, identified two groups of patients with different immune status and severity features. Conclusion: We demonstrated that a large, unexplored part of our genome, which codes for HERV/MaLR, may be linked to the host immune response. The identified set of HERV/MaLR probesets should be evaluated on a large scale to assess the relevance of these loci in the stratification of septic shock patients. This may help to address the heterogeneity of these patients.

Herpes DNAemia and TTV Viraemia in Intensive Care Unit Critically Ill Patients: A Single-Centre Prospective Longitudinal Study

“…In contrast, genes with a consistently lower expression in patients than in healthy volunteers, namely, CD40L ( CD154 ), STAT4 , IL7R ( CD127 ), CD127s , CD3D ( Figure 2H ), CD74 , and CX3CR1 , had an even lower expression in patients with viraemia. In addition, the expression of some retrotransposons previously associated with immunocompromised status and disease severity ( 24 , 33 ) was found to be associated with viraemia, namely, HERVE 4.1 (170369402HE41env; lower expression with worsening of disease, lower expression with viraemia), LTR40A (050286701-HERV0513; higher expression with worsening of disease, higher expression with viraemia), and MLT1I (021456001-MALR1017; higher with worsening, higher expression with viraemia).…”

The infection-tolerant white-footed deermouse tempers interferon responses to endotoxin in comparison to the mouse and rat

“…This or a similar phenomenon has been observed under other circumstances. In humans, there was heightened transcription of retrotransposons in patients with septic shock ( Mommert et al, 2020 ), as well as in peripheral blood mononuclear cells from human subjects experimentally injected with LPS ( Pisano et al, 2020 ). Bacteria like Staphylococcus epidermidis that express TLR2 agonists, such as lipoteichoic acid, promoted expression of ERVs, which in turn modulated host immune responses ( Lima-Junior et al, 2021 ).…”

Evaluation of the Molecular Mechanisms of Sepsis Using Proteomics

“…In the last decade, various omics techniques have been used for the study of sepsis, including genomics (6,7), transcriptomics (8)(9)(10), proteomics (7), and metabolomics (7,11). Since the completion of the Human Genome Project and accumulation of extensive genomic data, proteomics has become an integral component of the post-genomic era (12).…”