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Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Datum: 01.04.2020 Kategorie: 07 Fatigatio e.V. Autor: MKK (kanter)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disorder with many possible triggers. Human herpesvirus (HHV)–6 and HHV-7 are two infectious triggers for which evidence has been growing. To understand possible causative role of HHV-6 in ME/CFS, metabolic and antiviral phenotypes of U2-OS cells were studied with and without chromosomally integrated HHV-6 and with or without virus reactivation using the histone deacetylase inhibitor trichostatin-A. Proteomic analysis was conducted by pulsed stable isotope labeling by amino acids in cell culture analysis. Antiviral properties that were induced by HHV-6 transactivation were studied in virus-naive A549 cells challenged by infection with influenza-A (H1N1) or HSV-1. Mitochondria were fragmented and 1-carbon metabolism, dUTPase, and thymidylate synthase were strongly induced by HHV-6 reactivation, whereas superoxide dismutase 2 and proteins required for mitochondrial oxidation of fatty acid, amino acid, and glucose metabolism, including pyruvate dehydrogenase, were strongly inhibited. Adoptive transfer of U2-OS cell supernatants after reactivation of HHV-6A led to an antiviral state in A549 cells that prevented superinfection with influenza-A and HSV-1. Adoptive transfer of serum from 10 patients with ME/CFS produced a similar fragmentation of mitochondria and the associated antiviral state in the A549 cell assay. In conclusion, HHV-6 reactivation in ME/CFS patients activates a multisystem, proinflammatory, cell danger response that protects against certain RNA and DNA virus infections but comes at the cost of mitochondrial fragmentation and severely compromised energy metabolism.

Human herpesvirus (HHV)–6A and –6B are neurotropic viruses that carry stretches of telomeric repeats at both ends of their linear genome that facilitate their genome integration into human chromosomes to achieve latency (1). Chromosomally integrated HHV-6 (ciHHV-6) is at times genetically inherited (iciHHV-6) (2). Around 0.2–1% of humans carry iciHHV-6 (3), and 90–100% are infected by age 3 (4, 5). HHV-7 is another member of the betaherpesvirus family that shares similar genomic integration features with HHV-6 (6). HHV-6 and HHV-7 are frequently associated with several human diseases, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (7–9) that also involve mitochondrial dysfunction (10, 11). Mitochondrial dysfunction has long been predicted to play a crucial role in development and/or progression of ME/CFS. Alterations in mitochondrial dynamics, deficient mitochondrial ATP generation, and increased oxidative stress during ME/CFS have been reported (12, 13). Biophysical changes in cells from ME/CFS patients placed under osmotic stress have recently been used as an innovative diagnostic test for ME/CFS (14). However, the exact antecedent to mitochondrial modulation in ME/CFS is largely unknown. We have recently shown that HHV-6A reactivation induces mitochondrial fragmentation (15). In this study, we investigated potential infectious causes and molecular mechanism(s) behind mitochondrial dysfunction, likely resulting in the development and/or progression of ME/CFS, using HHV-6A reactivation as a model. Our results show a serum-transferrable innate immune activity in ME/CFS patients that induces a state of low mitochondrial activity accompanied by changes in mitochondrial dynamics tha might contribute to disease pathophysiology.