Pathogenic role of SARS-CoV-2-induced herpesvirus reactivations in post-COVID symptoms and their relation to chronic fatigue syndrome.

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is a complex disease with many potential unknown triggers. The infectious origin of ME/CFS is doubted but has never been experimentally validated. Recently, it has been observed that a large subset of patients who had recovered from SARS-CoV-2 infection are developing ME/CFS-like symptoms and are continuing to have ME/CFS-like clinical conditions even after several months post-infection. This has strengthened the idea of infectious origin behind ME/CFS. Mounting epidemiological evidence implicates Human herpesvirus 6 (HHV-6), HHV-7, and Epstein-Barr virus (EBV) as three highly probable infectious triggers for ME/CFS. Preliminary in vitro experiments with SARS-CoV-2 infection in human cultured cells show strong HHV-6 reactivation. This led us to a hypothesis that it may not be the SARS-CoV-2 that directly causes ME/CFS-like symptoms. Rather, regaining functional activity by latent herpesvirus genome post-SARS-CoV-2 infection might be a key factor for ME/CFS development. We have developed an elegant HHV-6 reactivation model system and would like to utilize this to test herpesvirus reactivation as a causative factor behind ME/CFS. Herpesviruses are widely prevalent in the human population and have different cell specificities. Hence, we aim to apply systems biology-based approaches, including inter-disciplinary methodologies, to understand the molecular mechanism(s) behind infection-induced cellular and mitochondrial dysfunction in ME/CFS.