Overview
- The endothelium, a single layer of epithelial cells, lines the inside of blood vessels and plays a crucial role in various processes such as blood flow control and clotting.
- Endothelial dysfunction, i.e. impaired function of the endothelium, has been demonstrated both in long COVID and ME/CFS, however there is speculation as to the causes.
- A recent review hypothesised that persistent herpesvirus infection may contribute to endothelial dysfunction and the persistence of symptoms, such as cognitive dysfunction, in ME/CFS.
- This hypothesis is bolstered by research showing similar physiological changes, such as reduced tissue perfusion (blood flow), associated with both herpesvirus infection and endothelial dysfunction.
- Herpesviruses, including Epstein-Barr virus (EBV) and HHV-6, can remain in a latent (inactive) form in cells, with the potential for reactivation.
- These viruses may cause changes to the endothelium leading to endothelial dysfunction through complex processes involved in latency (becoming inactive), rather than through active infection.
- The authors advocate for future research to determine whether endothelial cells from individuals with ME/CFS (and controls) are infected with herpesviruses. This could advance our understanding of the disease.
A deeper look
Both endothelial dysfunction (impaired function of blood vessel lining known as the endothelium) and herpesviruses are topics of interest in ME/CFS research, though studies linking these subject areas remains sparse. A review by researchers from Stellenbosch University, South Africa, explored whether a potential relationship between herpesvirus infection and endothelial dysfunction may contribute towards the underlying mechanisms and manifestation of ME/CFS symptoms such as cognitive dysfunction. Examining a wealth of literature, including studies related to other chronic conditions such as multiple sclerosis, the researchers hypothesise that “chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation”. In other words, herpesvirus infection could lead to endothelial dysfunction which contributes to the manifestation of ME/CFS. The researchers state that the review “offers conceptual advances” and underscores the necessity for further research into the area.
Exploring the link between herpesviruses and endothelial dysfunction in ME/CFS
Whilst the “etiological cause” of ME/CFS is not known, “viral infection is believed to be a precipitating factor, and its pathology is very much associated with viral activity”. Herpesviruses are the most implicated type of viruses in ME/CFS, nevertheless, it is difficult to elucidate their mechanistic role in the disease, as “the majority of the global population is infected with herpesviruses.”
Endothelial dysfunction is another “prominent characteristic of ME/CFS pathology”, and has been discussed, alongside the broader category of vascular dysfunction (impaired function of blood vessels), in several studies related to ME/CFS, and long COVID research. According to the researchers, whilst endothelial dysfunction has been linked with “impaired circulatory function, reduced tissue oxygen supply, and unmet metabolic demands” in ME/CFS, research is limited into whether there is a relationship between herpesviruses and endothelial dysfunction in ME/CFS. The authors of the review explored this topic, focussing on Epstein-Barr virus (EBV) – a type of herpesvirus otherwise known as HHV-4, and HHV-6.
Viral latency
The review proposes endothelial cells of individuals with ME/CFS may be infected by herpesviruses to some extent. Herpesviruses are able to establish latency – a state where a virus remains in a dormant (inactive) state within cells and viral replication does not occur. It is possible for a virus in latent form to be reactivated as a result of various triggers. There is mixed evidence to suggest that herpesviruses establish latency in endothelial cells.
The researchers emphasise that herpesvirus latency is not passive, rather is a complex process involving various proteins and molecules, genetic materials, and immune system activity. Therefore, it is worth exploring whether the processes surrounding herpesvirus latency might also bring about “specific defects” in the endothelium. As latent infection “exerts pathological effects on the host”, herpesvirus reactivation/active infection “may not be necessary for the manifestation of ME/CFS symptoms.”
Symptom persistence
Herpesvirus infection of endothelial cells may explain the chronicity of ME/CFS symptoms, as dysfunctional endothelial cells may persist over time. The endothelium has a low turnover rate, with the entire population of endothelial cells replaced every six years, although rates can vary according to the specific tissue. Hence it is possible that viral-induced dysfunction caused herpesvirus infection may continue throughout the life of the endothelial cell. Furthermore, the review mentions that EBV and HHV-6 can inhibit apoptosis (programmed cell death), extending the lifespan of dysfunctional endothelial cells. Thus, persistent endothelial dysfunction could tie in with the persistent symptoms seen in ME/CFS, and endothelium can be found in every organ system, “endothelial dysfunction might account for the multi-organ and systemic nature of ME/CFS pathology.”
Herpesviruses and endothelial dysfunction – the evidence
The researchers compiled extensive evidence of connections between herpesvirus infection and endothelial dysfunction, which also involved drawing insights from diseases such as scleroderma and multiple sclerosis.
Findings/areas explored include (but are not limited to) –
- EBV promotes increased expressions of markers associated with vascular injury
- Influence of EBV on endothelial microenvironment
- EBV damages endothelial cellular junctions/barriers
- EBV- and HHV-6-infected endothelial cells promote inflammation
- HHV-6 associated with a greater extent of endothelial damage than human cytomegalovirus (HCMV)
- HHV-6 infects endothelial cells in vasculature of central nervous system
How might the pathological characteristics of ME/CFS align with the hypothesis?
Reduced cerebral blood flow has been observed in patients with ME/CFS, “even in those without tachycardia and hypotension”. The researchers suggest that “viral infection of vascular cells, such as ECs [endothelial cells] and smooth muscle cells, and neurons might contribute to the blood flow and perfusion abnormalities of ME/CFS”. They bolster this statement by pointing to several studies that suggest impaired tissue perfusion has been associated both with endothelial dysfunction and with herpesvirus infection.
The researchers have previously published research suggesting that some individuals with ME/CFS present with a hypercoagulable state i.e. an increased tendency to develop blood clots. As endothelial cells participate in coagulation, “minor cellular disturbances” can have significant effects on clotting processes. They further point to studies that suggest HHV-6 infection is associated with abnormal clotting, extrapolating that “there is reason to suspect that the clotting and platelet abnormalities noted in ME/CFS arise from the consequences of herpesvirus-infected ECs, as well as other procoagulant effects of herpesviruses independent of endothelial cells.”
Endothelial dysfunction has been associated with cognitive dysfunction in a number of conditions including vascular dementia, type 2 diabetes, and sleep apnoea, hence the researchers seem to suggest a potential association in the case of ME/CFS. Furthermore, herpesviruses are capable of infecting endothelial cells in the brain, with HHV-6 associated with cognitive impairments in certain conditions and EBV infection “posited to contribute neuroinflammation and subsequent neurological issues in ME/CFS.”
Conclusion
The researchers hypothesize that herpesvirus infection of endothelial cells “might be an important, overlooked phenomenon that can, in part, account for the pathophysiology and symptoms of ME/CFS”. They advocate for future research to determine whether endothelial cells from individuals with ME/CFS (and controls) are indeed infected with herpesviruses, and suggest the analysis of endothelial cells/vascular tissues cells in regions of the body such as brain and smooth muscle.
It is important to recognise that the mechanism proposed is not proven. The researchers acknowledge this, stating – “ME/CFS is an extremely heterogeneous disease with numerous proposed etiological factors, with various subpopulations experiencing specific symptoms and presenting a clinically distinct phenotype. Hence, this idea may not explain the symptoms of all ME/CFS subpopulations—further work is required in this context.” Furthermore, pathogens other than herpesviruses could be influencing endothelial function. Nevertheless, they encourage “a more refined focus on herpesviruses and endothelial function and health in ME/CFS”, and also suggest potential implications for long COVID research.
Read more about endothelial dysfunction in ME/CFS and long COVID
