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

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.

Operation of mitochondrial machinery in viral infection-induced immune responses

“…Strikingly, the results show that the dysfunction of the mitochondrial enzyme cytochrome C oxidase (CO, composed predominantly of mtDNA encoded subunits) precedes that of succinate dehydrogenase (composed entirely of nuclear encoded subunits). Treatment with minocycline leads to increases in the CO1 transcript abundance, sustained CO activity and cell viability [85]. This study highlights the significance of mitochondrial damage that occurs during the very early stages of HSV-1 infection and demonstrates the usefulness of minocycline as a potential therapeutic agent for patients with herpes simplex encephalitis.…”

“…By examining limited postmortem brain samples from patients with herpes simplex encephalitis, Wnek et al observed a preferential reduction in mitochondrial genome encoded transcripts in the genomewide transcriptomic study [85]. There is also a preferential loss of mitochondrial function among mtDNA encoded components in primary human astrocytes infected by HSV-1 [85].…”

“…By examining limited postmortem brain samples from patients with herpes simplex encephalitis, Wnek et al observed a preferential reduction in mitochondrial genome encoded transcripts in the genomewide transcriptomic study [85]. There is also a preferential loss of mitochondrial function among mtDNA encoded components in primary human astrocytes infected by HSV-1 [85]. Strikingly, the results show that the dysfunction of the mitochondrial enzyme cytochrome C oxidase (CO, composed predominantly of mtDNA encoded subunits) precedes that of succinate dehydrogenase (composed entirely of nuclear encoded subunits).…”

Clinical effects of chemical exposures on mitochondrial function

“…The contribution of mitochondrial dysfunction has been reported in major environment-related multifactorial diseases, such as respiratory disease (Bialas et al, 2016), viral infections (Wnek et al, 2016), neurological disorders (Giannoccaro et al, 2017, Swerdlow et al, 2017), cardiovascular diseases (Sabbah, 2016), and cancer (Srinivasan et al, 2017). Although harmful exposure to environmental pollutants is ubiquitous among all populations, disease manifestation occurs in only a subset of the population.…”

Decoding the association between herpes simplex virus and antibody‐mediated encephalitis

“…The rapid development of transcriptomic and proteomic approaches offers an opportunity to identify specific patterns of biomarkers involved in infective and antibody‐mediated encephalitis. Such techniques are already beginning to provide insight into mechanisms of injury and identify potential adjunctive treatments for HSE …”