Coxsackievirus-B4 Infection Can Induce the Expression of Human Endogenous Retrovirus W in Primary Cells.

Sandrine Levet,Arthur Dechaumes,Valéry Gmyr,Jennifer Varghese,Didier Hober,Antoine Bertin,Benjamin Charvet,Justine Pierquin,Julie Kerr-Conte,Famara Sane,François Pattou,Govindakarnavar Arunkumar,Hervé Perron

doi:10.3390/microorganisms8091335

Abstract

Human Endogenous Retrovirus W Envelope (HERV-W ENV) mRNA or protein can be found in peripheral blood mononuclear cells (PBMCs) and exocrine pancreas of patients with type 1 diabetes (T1D). Further, previous observations have shown an association between enteroviral infection and development of T1D; specifically, coxsackievirus-B (CV-B) has been detected in the blood and pancreas of patients with T1D. Notably, viruses can activate HERV-W expression. Hence, we evaluated the effect of CV-B4 infection on HERV-W ENV mRNA expression. Primary human pancreatic ductal cells were obtained from five brain-dead donors. In the pancreatic cells of three donors, the HERV-W ENV mRNA level measured using RT-qPCR was upregulated upon CV-B4 infection. The HERV-W ENV protein was detected in the infected cells using the immunoblot assay. In human PBMCs inoculated with CV-B4 or when CV-B4 was incubated with an enhancing serum, the HERV-W ENV mRNA level was higher than the background RNA level. In monocyte-derived macrophages obtained from 5 of 13 donors, the HERV-W ENV mRNA level was higher in cultures inoculated with CV-B4 than in the control. Therefore, CV-B4 can upregulate or induce the transcription of a certain HERV-W ENV copy (or copies) in primary cell cultures, such as monocytes, macrophages, and pancreatic cells.

Highlights

Human Endogenous Retroviruses (HERVs) are vestigial sequences endogenized in primate germinal cells and transmitted across generations over the course of evolution [1]
In light of recent discoveries on the activation of HERV-W ENV in peripheral blood mononuclear cells (PBMCs) and pancreatic cells of patients with type 1 diabetes (T1D) [3] and considering the association between CV-B, especially CV-B4, and T1D, we aimed to evaluate the potential effect of CV-B4 on the expression of HERV-W ENV in these cells
As experimentation with primary cultures implicitly results in asynchronous infections and variable kinetics of HERV-W transcriptional induction between cells and cultures, we chose to compare peaks of mRNA quantification to address the issue of HERV-W transcriptional activation by CV-B4 (Figure 2b)

Summary

Introduction

Human Endogenous Retroviruses (HERVs) are vestigial sequences endogenized in primate germinal cells and transmitted across generations over the course of evolution [1]. Some belong to the pool of physiological genes; Syncytin-1, which is an envelope protein of HERV-W, is involved in placentation [4]. In contrast with domesticated HERV copies, which have physiological roles like Syncytin-1, HERVs may be involved in the pathogenesis of some diseases, such as autoimmune diseases, relying on a complex interplay between environmental and genetic factors. HERVs may assist in drawing a link between environmental factors, genetic factors, and pathogenic mechanisms of diseases such as multiple sclerosis (MS) or amyotrophic lateral sclerosis [7]. The envelope protein of HERV-W, termed HERV-W ENV, is being studied in autoimmune diseases, given its immunopathogenic properties [8]. In patients with T1D, HERV-W ENV was detected widespread or in clusters in the exocrine pancreas and in the vicinity of Langerhans islets [3]

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