Herpes simplex encephalitis is linked with selective mitochondrial damage; a post-mortem and in vitro study.

Małgorzata Wnęk,Patrick F Chinnery,Colin Smith,Carmen Rodriguez-Martinez,Zarini Ismail,Lorenzo Ressel,Tom Solomon,Anja Kipar,Michael J Griffiths,Beate Sodeik,Emanuele Ricci,Julio Cesar Villalvazo Guerrero

doi:10.1007/s00401-016-1597-2

Abstract

Herpes simplex virus type-1 (HSV-1) encephalitis (HSE) is the most commonly diagnosed cause of viral encephalitis in western countries. Despite antiviral treatment, HSE remains a devastating disease with high morbidity and mortality. Improved understanding of pathogenesis may lead to more effective therapies. Mitochondrial damage has been reported during HSV infection in vitro. However, whether it occurs in the human brain and whether this contributes to the pathogenesis has not been fully explored. Minocycline, an antibiotic, has been reported to protect mitochondria and limit brain damage. Minocycline has not been studied in HSV infection. In the first genome-wide transcriptomic study of post-mortem human HSE brain tissue, we demonstrated a highly preferential reduction in mitochondrial genome (MtDNA) encoded transcripts in HSE cases (n = 3) compared to controls (n = 5). Brain tissue exhibited a significant inverse correlation for immunostaining between cytochrome c oxidase subunit 1 (CO1), a MtDNA encoded enzyme subunit, and HSV-1; with lower abundance for mitochondrial protein in regions where HSV-1 was abundant. Preferential loss of mitochondrial function, among MtDNA encoded components, was confirmed using an in vitro primary human astrocyte HSV-1 infection model. Dysfunction of cytochrome c oxidase (CO), a mitochondrial enzyme composed predominantly of MtDNA encoded subunits, preceded that of succinate dehydrogenase (composed entirely of nuclear encoded subunits). Minocycline treated astrocytes exhibited higher CO1 transcript abundance, sustained CO activity and cell viability compared to non-treated astrocytes. Based on observations from HSE patient tissue, this study highlights mitochondrial damage as a critical and early event during HSV-1 infection. We demonstrate minocycline preserves mitochondrial function and cell viability during HSV-1 infection. Minocycline, and mitochondrial protection, offers a novel adjunctive therapeutic approach for limiting brain cell damage and potentially improving outcome among HSE patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1597-2) contains supplementary material, which is available to authorized users.

Highlights

Herpes simplex virus (HSV) is one of the most common causes of viral encephalitis in western countries
Observing a marked loss of mitochondrial transcripts among herpes simplex encephalitis (HSE) cases, we examined whether the reduction of the mitochondrial protein (CO1) was topographically linked to the presence of Herpes simplex virus type-1 (HSV-1) proteins in the HSE brain tissue
HSV-1 antigen staining of hippocampal HSE tissue confirmed, the astrocyte intranuclear inclusions were composed of viral particles (Fig. 1f)

Summary

Introduction

Herpes simplex virus (HSV) is one of the most common causes of viral encephalitis in western countries. HSV-1 type 1 (HSV-1) is the predominant cause of herpes simplex encephalitis (HSE). Improved understanding of the pathogenesis of HSE and more effective treatments are required [47, 52]. Multiple studies have described the brain pathology in human HSE cases and animal models of HSV-1 infection. Studies examining the pathogenesis of HSE have tended to use animal in vivo and in vitro models or transformed human cell lines derived from cells outside the brain [13, 20, 45]. And/or functionally distinct from the human brain, such models may not accurately reflect human HSE

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