An understanding of the immune dysfunction in susceptible people who develop the post-viral fatigue syndromes Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID

Abstract

Viral infection in most people results in a transient immune/inflammatory response resulting in elimination of the virus and recovery where the immune system returns to that of the pre-infectious state. In susceptible people by contrast there is a transition from an acute immune response to a chronic state that can lead to an ongoing lifelong complex post-viral illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. This susceptibility is proposed to be genetic or be primed by prior health history. Complex abnormalities occur in immune cell functions, immune cell metabolism and energy production, and in cytokine immune modulator regulation. The immune system of the brain/central nervous system becomes activated leading to dysfunction in regulation of body physiology and the onset of many neurological symptoms. A dysfunctional immune system is core to the development of the post-viral condition as shown with diverse strategies of immune profiling. Many studies have shown changes in numbers and activity of immune cells of different phenotypes and their metabolism. Immune regulating cytokines show complex altered patterns and vary with the stage of the disease, and there are elements of associated autoimmunity. These complex changes are accompanied by an altered molecular homeostasis with immune cell transcripts and proteins no longer produced in a tightly regulated manner, reflected in the instability of the epigenetic code that controls gene expression. Potential key elements of the altered immune function in this disease needing further exploration are changes to the gut-brain-immune axis as a result of changes in the microbiome of the gut, and viral reactivation from latent elements of the triggering virus or from a prior viral infection. Long COVID, an Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-like illness, is the post-viral condition that has arisen in large numbers solely from the pandemic virus Severe Acute Respiratory Syndrome Coronovirus-2. With over 760 million cases worldwide, an estimated ~100 million cases of Long COVID have occurred within a short period. This now provides an unprecedented opportunity to understand the progression of these post-viral diseases, and to progress from a research phase mainly documenting the immune changes to considering potential immunotherapies that might improve the overall symptom profile of affected patients, and provide them with a better quality of life.

A pilot study on the immune cell proteome of long COVID patients shows changes to physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndrome

“…Subgroups have been suggested for ME/CFS patients in multiple publications 59 – 62 . Indeed, we have examined individual patients by a precision medicine approach within a well characterized homogeneous small subgroup (age/sex, length of illness, relative functional activity levels) and have found individual patient differences in the molecular changes that still results in a very similar pathophysiology 6 , 21 . We believe this reflects the individual’s health history and genetic background that makes them susceptible to mount an inappropriate but immune response with individual variations to an external stressor that becomes chronic and spreads to involve the brain and CNS 14 , resulting in the ongoing neurological symptoms that characterise the condition.…”

“…How does the occurrence of clinical phenotypes interfere with obtaining an accurate understanding of how closely related LC and ME/CFS are and on developing therapeutic strategies to improve the health of patients? Multiple papers have documented changes in both peripheral immune cell numbers and their activities, and the up or down regulation of cytokines 21 . While there may be individual differences dependent upon the viral trigger in LC or heterogeneous triggers in ME/CFS, this is likely also to reflect variations among the individual patients themselves according to their genetic background.…”

“…The disturbed functions of the CNS result in multiple neurological symptoms, and in poor brain regulation of body physiology. A number of studies have documented chronic dysregulation of the immune cell function involving multiple cell types, and cytokines in ME/CFS 15 – 21 , and now more recently in LC 22 – 25 . In ME/CFS, multiple disturbances have been reported in the molecular homeostasis of the transcriptomes 26 – 28 , proteomes 29 – 31 , and DNA methylomes 32 – 36 of peripheral blood mononuclear cells (PBMC) that include lymphocytes (T cells, B cells, NK cells) and monocytes 37 , but not as yet in LC.…”

Immune cell proteomes of Long COVID patients have functional changes similar to those in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Subgroups have been suggested for ME/CFS patients in multiple publications [59][60][61][62] . Indeed, we have examined individual patients by a precision medicine approach within a well characterized homogeneous small subgroup (age/sex, length of illness, relative functional activity levels) and have found individual patient differences in the molecular changes that still www.nature.com/scientificreports/ results in a very similar pathophysiology 6,21 . We believe this reflects the individual's health history and genetic background that makes them susceptible to mount an inappropriate but immune response with individual variations to an external stressor that becomes chronic and spreads to involve the brain and CNS 14 , resulting in the ongoing neurological symptoms that characterise the condition.…”

“…The disturbed functions of the CNS result in multiple neurological symptoms, and in poor brain regulation of body physiology. A number of studies have documented chronic dysregulation of the immune cell function involving multiple cell types, and cytokines in ME/CFS [15][16][17][18][19][20][21] , and now more recently in LC [22][23][24][25] . In ME/CFS, multiple disturbances have been reported in the molecular homeostasis of the transcriptomes 26-28 , proteomes [29][30][31] , and DNA methylomes [32][33][34][35][36] of peripheral blood mononuclear cells (PBMC) that include lymphocytes (T cells, B cells, NK cells) and monocytes 37 , but not as yet in LC.This current study analysed the PBMC proteomes of post-viral fatigue LC patients whose illness had lasted for one year, compared with age/sex matched healthy controls.…”