Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented as having arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events. Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation. What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long. The severity of the symptoms frequently fluctuates through relapse recovery periods, with brain-centered symptoms of neuroinflammation, loss of homeostatic control, "brain fog" affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address. We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctional blood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles. Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur. By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2. We believe the ME/CFS-like ongoing effects of Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with some unique signaling, resulting from the pathology of the initial SARS-CoV-2 infection. The fact that there are very similar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both.

Keywords: Long COVID; ME/CFS; disease persistence; neuroinflammation; relapse; systemic inflammation.

Figure 1

Hypothesis and model for onset of ME/CFS and its progression to a chronic sustained illness with relapse/partial recovery phases: signaling pathways between the CNS and the periphery that maintain the illness. Following an initial external stressor event systemic immune/inflammatory responses are activated, these are communicated to the CNS via inflammatory, and gateway reflexes and possibly an increase in permeability of the BBB. Neuroinflammation is activated affecting the stress center within the PVN of the hypothalamus and leads to a wide range of neurological symptoms that feedback to the periphery via disturbance of homeostasis and the stress activated HPA axis that becomes dysfunctional with chronic activation. The systemic physiology and molecular homeostasis are then chronically affected through important cellular functions like mitochondrial energy production metabolic activity and a continuation of immune/inflammatory reactions. External life stressors that feed into a disturbed PVN not only maintain the ME/CFS but also act to precipitate relapses.

Figure 2

Three key elevated transcripts in immune cells from ME/CFS patients are involved in inflammation. The most enhanced transcripts from RNA-seq data (p-value 0.01/fold change 1.5) in PBMCs from 10 ME/CFS patients compared with 10 age/gender matched healthy controls shown in the upper part of the figure were Interleukin 8 (IL8) a proinflammatory cytokine, and two inhibitory transcripts, NF-κB inhibitor alpha (NIFKBIA), and tumor necrosis factor alpha-induced protein 3 (TNFAIP3). These were validated by determining the mean fold changes by RT-qPCR (±SEM) between the patient group and the healthy control group, and similar fold changes were determined. *p < 0.01.

Figure 3

The percent dynamic variability of unique CpG methylations of the epigenetic code in ME/CFS patients and an age gender matched healthy control over a year. DNA methylomes were analyzed at 5 time points for 2 ME/CFS patients and an age/gender matched healthy control. Each point (A-E) represents the statistically significant unique differentially methylated CpG sites at that time point in a longitudinal study lasting 1 year, expressed as a percentage of the total differentially methylated sites determined for that time point (each of A to E). (A) The two patients showed a consistent variability of 2–3% over the time course whereas the control variability was constant from sample to sample but 10–20-fold lower (0.15%) than in the patients. (B) Each patient suffered a relapse (Time points B, and B, and C, respectively) and in both cases the differentially methylated changes at the relapse time point(s) showed a signature of an enhanced immune response associated with the relapse.

Figure 4

Mechanisms proposed to facilitate the onset of ME/CFS and its progression to a chronic sustained illness with relapse/partial recovery phases. This figure summarizes the mechanisms discussed in the text proposed to have a possible function in sustaining ME/CFS and facilitating relapses.