title: 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.
authors.affiliation: Brain Infections Group, Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE, UK.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Wnęk
authors.affiliation: Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool Science Park IC2, Liverpool, L3 5RF, UK.|Veterinary Pathology, School of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, CH64 7TE, UK.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Ressel
authors.affiliation: Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool Science Park IC2, Liverpool, L3 5RF, UK.|Veterinary Pathology, School of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, CH64 7TE, UK.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Ricci
authors.affiliation: Brain Infections Group, Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE, UK.
authors.forename: Carmen
authors.initials: C
authors.lastname: Rodriguez-Martinez
authors.affiliation: Institute of Virology, Hannover Medical School, 30625, Hannover, Germany.|German Centre for Infection Research (DZIF), Hannover, Germany.
authors.forename: Julio Cesar Villalvazo
authors.initials: JC
authors.lastname: Guerrero
authors.affiliation: Brain Infections Group, Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE, UK.
authors.forename: Zarini
authors.initials: Z
authors.lastname: Ismail
authors.affiliation: Academic Neuropathology, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool Science Park IC2, Liverpool, L3 5RF, UK.|Veterinary Pathology, School of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, CH64 7TE, UK.|Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, 8057, Zurich, Switzerland.
authors.forename: Anja
authors.initials: A
authors.lastname: Kipar
authors.affiliation: Institute of Virology, Hannover Medical School, 30625, Hannover, Germany.|German Centre for Infection Research (DZIF), Hannover, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Sodeik
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: Brain Infections Group, Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE, UK.|Department of Neurology, The Walton Centre NHS Foundation Trust, Fazakerley, Liverpool, L9 7LJ, UK.|National Institute for Health Research, Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, L69 7BE, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Solomon
authors.affiliation: Brain Infections Group, Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE, UK. griffmj@liverpool.ac.uk.|National Institute for Health Research, Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, L69 7BE, UK. griffmj@liverpool.ac.uk.|Department of Neurology, Alder-Hey Children's NHS Foundation Trust, West Derby, Liverpool, L12 2AP, UK. griffmj@liverpool.ac.uk.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Griffiths
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D001344:Autopsy / Q000379:methods; D001921:Brain / Q000473:pathology* / Q000821:virology; D020803:Encephalitis, Herpes Simplex / Q000473:pathology* / Q000821:virology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D018139:Simplexvirus
chemical_list: D000998:Antiviral Agents
keywords: Gene-expression; Herpes simplex virus encephalitis; Human; Minocycline; Mitochondria