A new study by researchers from Linköping University-Sweden has shockingly found that SARS-CoV-2 infections can lead to epigenetic changes in the human host that contributes to various medical and health conditions seen in Long COVID.
The study findings were published in the peer reviewed journal: Clinical Epigenetics.
In this study the researchers have demonstrated that healthy COVID-19 convalescents carry a distinct DNA methylation (DNAm) pattern in their peripheral blood mononuclear cells (PBMC) without any shifts in PBMC cell population frequencies .
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To the best of our knowledge, this is the first report of epigenome-wide DNAm alterations in subjects with PACS. We and others have studied DNA methylation changes in response to acute COVID-19  and in healthy recoverees after the acute phase . The CpG sites with the most pronounced changes comparing PACS with CC19 were found in genes encoding SNORD3B, CETP and DLGAP.
SNORD3B belongs to a family of small nucleolar RNAs that have been suggested to be exploited by RNA viruses . CETP is a cholesterol metabolizing enzyme and CETP-inhibitors have been proposed as treatment option for COVID-19 .
DLGAP is a postsynaptic protein that binds dynein (DYNLL1), which in turns binds no less than 10 SARS-CoV-2 proteins. Several of the pathways that we found epigenetically modulated in PACS subjects, including Angiotensin II receptor, muscarinic receptors and histamine signalling pathways, are relevant for the symptomatic picture of PACS.
Angiotensin II has been shown to regulate the expression of ACE2 in neurons and SARS-CoV-2 binds to the ACE2 receptor via the S (spike) protein to enter cells.
Histamines have been demonstrated to play a role in PACS, as partial symptom relief was reported in PACS patients upon treatment with antihistamines .
The pathways regulated by muscarinic receptors CHRM1&3 play a role in odour perception and were found to be epigenetically modulated in patients with PACS. Auto-antibodies towards GPCR have been demonstrated in chronic fatigue syndrome (CFS)  and a recent review lists a number of auto-antibodies targeting GPCRs that were identified also in PACS .
We found a tendency of increased levels of CHRM3-specific IgG autoantibodies in our PACS cohort. Functionally active auto-antibodies are known to disturb the balance of neuronal and vascular activity and in fact, extracorporeal apheresis could reduce levels of autoantibodies and alleviate symptoms of CFS in a recent PACS study .
The finding of epigenetic modulation of the pathways of the same receptors for which auto-antibodies are described in PACS and CFS is intriguing and raises the question of a possible mechanistic relationship. Hypothetically, as part of the anti-viral defense, the host could down-modulate (either by creating autoantibodies or epigenetically) pathways exploited by the virus, which when they become persistently downregulated after viral clearance, may contribute to impairment of cellular functions.
In line with this idea, the PPI modules that we found to be epigenetically modulated include cellular processes that are central to vesicle formation, exemplified by the identified connection of PACSIN2 and sub-membrane actin remodeling (ARP2/3), which potentially contributes to the formation of new virus particles.
Another identified module with very strong interactions with SARS-CoV-2 involves NDUFA proteins, which regulate the NADH oxidase in mitochondria. Mitochondrial dysfunction was recently described in PACS  and our finding of an epigenetically modified module at the core of mitochondrial function warrants further investigation in PACS.
We cannot exclude the possibility that the PACS specific epigenetic signature is driven by a hidden SARS-CoV-2 reservoir. Studies including the epigenetic background and signatures in other than post viral fatigue syndromes are needed. The impact of vaccination on DNAm profiles is not possible to determine in the current study and should be evaluated in future analyses.
In summary, although limited by the number of subjects included and without information on the stability of the DNAm signature, the results of the present pilot study can generate hypotheses that may help to explain the pathophysiological mechanisms underlying PACS.
Hopefully, this could accelerate the development of preventive strategies and therapeutic options for PACS, which likely will persist longer than the COVID-19 pandemic itself.
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