Gottschalk et al. Infectious Agents and Cancer 2023, 18(1):7
https://doi.org/10.1186/s13027-023-00485-z

Infectious Agents and Cancer

Open Access

REVIEW

Potential molecular mechanisms of chronic
fatigue in long haul COVID and other viraldiseases
Carl Gunnar Gottschalk1,2, Daniel Peterson1, Jan Armstrong1, Konstance Knox2,3 and Avik Roy1,2*

Abstract
Historically, COVID-19 emerges as one of the most devastating diseases of humankind, which creates an unmanageable health crisis worldwide. Until now, this disease costs millions of lives and continues to paralyze human civilization’s
economy and social growth, leaving an enduring damage that will take an exceptionally long time to repair. While amajority of infected patients survive after mild to moderate reactions after two to six weeks, a growing population ofpatients suffers for months with severe and prolonged symptoms of fatigue, depression, and anxiety. These patientsare no less than 10% of total COVID-19 infected individuals with distinctive chronic clinical symptomatology, collectively termed post-acute sequelae of COVID-19 (PASC) or more commonly long-haul COVID. Interestingly, Long-haul
COVID and many debilitating viral diseases display a similar range of clinical symptoms of muscle fatigue, dizziness,depression, and chronic inflammation. In our current hypothesis-driven review article, we attempt to discuss themolecular mechanism of muscle fatigue in long-haul COVID, and other viral diseases as caused by HHV6, Powassan,
Epstein–Barr virus (EBV), and HIV. We also discuss the pathological resemblance of virus-triggered muscle fatigue withmyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Keywords IFNγ, Microglia, CD4+ and ­CD8+ T cells, Mitochondria*Correspondence:
Avik Roy
aroy@simmaron.com
Full list of author information is available at the end of the article© The Author(s) 2023, corrected publication 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes
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Gottschalk et al. Infectious Agents and Cancer 2023, 18(1):7

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Graphical Abstract

Introduction
The role of viral infection in muscle fatigue has been
debated for a long in the field of ME/CFS [1]. ME/CFS
is a chronic inflammatory disease characterized bysevere muscle weakness, fatigue, pain, lightheadedness,and brain fog [2]. One of the most debilitating symptoms of ME/CFS is post-exertional malaise (PEM), in
which a patient suffers severe muscle fatigue and cognitive-, and orthostatic- exertions after mild exercise. This
severe worsening of symptoms can cause a patient tobe bedridden for a long time ranging from 24 h to several months [3, 4]. Although, the underlying molecularmechanism of severe muscle fatigue in ME/CFS is notknown, a growing body of evidence suggests that intracellular inflammation and exaggerated productions ofinflammatory mediators might contribute to the pathogenesis of muscle fatigue via promoting the degenerationof skeletal muscle cells and also inhibiting the differentiation of muscle progenitor cells [5, 6]. However, it is notknown how the inflammation is initiated. In this context, a “ hit-and-run” mechanism of viral infection could
be critical in which a transient viral infection is considered to potentiate a series of inflammatory events causing a sustained immunological disturbance [7]. A “virus

reactivation theory” could be another mechanism [8],which suggests that the reactivation of viruses including
EBV and HHV6 followed by a cascade of inflammatory
events might contribute to the pathogenesis of ME/CFS[1]. Despite these competing hypotheses, the role of viral
infection in the pathogenesis of muscle fatigue cannot bedisregarded. Interestingly, a recent pandemic of COVID19 also exhibits persistent symptoms of fatigue and weakness in approximately 10% of its survivors reiterating thepotential role of virus infection in the pathogenesis ofchronic fatigue syndrome [9]. Our current speculative
review article discusses how HHV6, Powassan, EBV, HIV,and SARS-CoV2 viral infections adopt a common immunological mechanism that possibly leads to the debilitating muscle fatigue.
HHV6 and chronic fatigue syndrome

The potential association between HHV6 and chronic
inflammation was first introduced in 1992 by Buchwald
et al. [10] when a cohort of 259 HHV6-infected patientswas diagnosed with severe lymphocytic activation andcognitive impairment. Although, that study was controversial [11] to prove the link between chronic fatigue syndrome (CFS) and HHV6, in the same year, Kato et al. [12]Gottschalk et al. Infectious Agents and Cancer 2023, 18(1):7

reported a case study with a 31-year-old woman who wasinitially admitted with CFS, was turned out to be positive
with a high titer of anti-HHV6 antigen. Later on, a PCRbased study [13] identified strong upregulations of HHV6
A and B mRNAs in 7 of 13 CFS patients with high titerof HHV6 early antigen demonstrating a strong correlation between HHV6 infection and CFS. Furthermore, astrong upregulation of IgM antibody against HHV6 early
antigen (EA) [14] in 93 of 154 CFS patients (60%) [15]established another possible link between HHV6 and
CFS. Although the molecular mechanism of HHV6 infection and fatigue was still unclear, HHV6 was known to
induce an acute immunosuppressive response. Althoughboth HHV6-A and-B strains infect CD4 + T helper and­CD8+ cytotoxic T cells [16], upon infection, HHV6

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selectively suppresses the expression of IL12 and inhibits
Th1 polarization of CD4 + T cells [16]. In infected CD4 +T cells, HHV6 also suppresses the proliferative responseby downregulating the expression of IL2 [17] and augmenting cell cycle arrest [18]. All these events induce
apoptotic signals to ­CD4+ T cells (Fig. 1). In response tothese apoptotic T cells, macrophages perform phagocytosis and augment an anti-inflammatory “immunotolerant” microenvironment characterized by high levelsof TGF-β and IL-10 [19]. In addition, a death response
to CD4 + T cells causes acute suppression of anti-viral
IFN-γ production [20, 21]. Interestingly, reduced IFN-γ
and increased IL-10 are historically known to suppress
inflammation [22, 23]. Therefore, the role of acute HHV6
infection in inducing inflammation seems elusive. One

Fig. 1 Potential mechanism of muscle fatigue is related to acute immunosuppressive and chronic inflammatory mechanisms of HHV6 viral
infection. Acute infection of HHV6 (Blue shade) causes immunosuppression. During that phase, virus-infected CD4 + Th1 and CD8 + Tc cells
undergo apoptosis (#1) following phagocytosis (#2) by macrophages (Mφ). During phagocytosis, Mφ release TGFβ and IL10 as a part of theimmune tolerance response (#3). IL10 and IL4 are also secreted from Th2 cells during activation of F­ OXP3+ve regulatory T cells. Together, there is an
immunosuppressive response marked with reduction of inflammatory cytokines (#4). However, during chronic inflammation and viral reactivation(Red shade), a subset of persistently infected Th1 cells escape apoptosis, undergo clonal proliferation (IL2 and IL12) (#1), engage in crosstalk with
Mφ, build up inflammatory milieu (#2), generate oxidatively (ROS = reactive oxygen species) and nitrosative stress (NO = nitric oxide) (#3). These
inflammatory T cells also infiltrate through the blood–brain barrier (BBB), interacts with microglia causing CNS inflammation, demyelination ofoligos, demyelination of nerve fibers (#4), and finally leads to the impaired nerve conduction, muscle weakness, and fatigue. FOXP3 = forkhead box
P3; A master transcription factor in the development and function of regulatory T cells

Gottschalk et al. Infectious Agents and Cancer 2023, 18(1):7

potential mechanism could be the escape of persistently
infected ­CD4+ T cells from the above-mentioned acuteapoptotic pathway that potentially stimulate an inflammatory response in macrophages and glial cells. A recent
report also suggests that HHV6A directly stimulates the
inflammation and migration of microglial cells via activation of TREM2 and ApoE [24].Therefore, active HHV6
infection, but not an acute immunosuppressive event,
may be directly responsible for responsible for the microglial activation [25], and possible demyelination [26]. Furthermore, a recent study [27] identified that patients withdemyelination in CNS displayed HHV6-immunoreactive
oligoclonal bands in their cerebrospinal fluid indicating a potential link between multiple sclerosis (MS)-like
encephalopathy and HHV6-infection.
Nevertheless, the upregulation of 8-hydroxy-2′deoxyguanosine (8h2dg) [28], a DNA stress marker, in the
CSF of HHV6 encephalopathy patients and a significant
recovery after FDA-approved ALS-drug Edarvone further confirmed the presence of encephalopathic response
in HHV6 patients. That study demonstrated that 43.7% of
HHV6 encephalopathy subjects had higher 8h2dg. Clinical symptoms such as muscle fatigue, sleep disturbance,
problems with balance, impaired mobility, and seizures
are pathological hallmarks of an encephalopathy [29, 30].
Therefore, combined with the mechanism of persistentimmune activation, HHV6 infection could also trigger
a CNS-specific stress response resulting in microglial
inflammation [24], demyelination [31], oxidative stress[32], and neuronal damage [33], which might lead to theclinical manifestations of cognitive deficit, emotional
disabilities, and muscle fatigue. HHV6 infection directly
or indirectly triggers neurodegeneration. In an indirect
mechanism, HHV6A promotes microglial expression ofamyloid beta (Aβ) [24], the secretion of phospho-tau [24],and the induction of IL-1β. Moreover, HHV6 directly
causes apoptosis of cerebellar Purkinje cells [34] suggesting its direct role in neurodegeneration. As a mechanism,
the disruption of TLR4 signaling [35] and activation of
TLR9 [36] followed by activation of nuclear factor κB(NF-κB) [37] might play key roles in inducing pro-inflammatory signaling events. HHV6 infection also profoundly
contributes to central and peripheral demyelination.
HHV6 virions directly infect oligodendroglial progenitor
cells (OPCs) and cause cell cycle arrest at G1/S phase andinhibit its maturation to oligodendrocytes [38]. Other
reports suggest that HHV-6A latency gene U94 directly
inhibits migration and myelination of OPCs [39]. Similar
to the situation in the CNS, HHV6 also induces peripheral demyelination by direct infection of the peripheral
nervous system in dorsal sensory ganglia [40, 41].

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Taken together, both the central and peripheral mechanisms of HHV6-induced demyelination result in the progressive loss of nerve conduction to the synaptic terminalat the neuromuscular junction resulting in the muscle
weakness and fatigue (Fig. 1).
Powassan virus encephalitis and chronic fatigue

Powassan virus (POWV) encephalitis was first reported
in 1958, when the titer of POWV, a neuroinvasive arbovirus, was detected from the brain autopsy of a young boy
who died in Powassan, Ontario [42]. It is a tickborne flavivirus-induced [43, 44] disease that displays a wide spectrum of neuroinflammatory responses [45] in the brain
and spinal cord including compromised blood–brain
barrier integrity, enhanced infiltration of inflammatory T
cells [46, 47], severe microglial activation [47], and demyelination [48] of oligodendrocytes resulting neuronal toxicity. While it is not known if POWV can induce a similar
acute immunosuppressive mechanism as seen in HHV6,
a recent study [49] demonstrated that there is a robust
proliferation of reactive Th1 cells in the spleens of the
POWV-infected mice. This finding suggests that, in contrast to HHV6, POWV acutely induces the inflammatory
response in the early phase of infection. During the acutephase of infection, there is an activation of innate immunity (Fig. 2) for the protection against POWV infection.
One such mechanism includes the activation of B cells
and the subsequent expression of IgM antibodies. Indeed,elevated IgM antibodies have been identified in both CSF
and sera of acute POWV-infected patients [44]. IgM
antibody directly induces cytotoxicity of virus-infected
cells. Another protective mechanism could include theacute activation of natural killer (NK) cells and naturalkiller T (NKT) cells [50] followed by the release of antiviral cytokine IFNγ (Fig. 2). Although this mechanism is
yet to be established in POWV infection, another tickborne bacterial disease, namely Lyme disease [51] hasbeen shown to directly activate NK cells in tick-borne
encephalitis. Although, direct association of POWV withNK cells has yet to be established, infections of other flaviviruses such as West Nile virus (WNV), dengue virus(DENV), yellow fever virus (YFV), Japanese encephalitis
virus (JEV), and tick-borne encephalitis virus (TBEV),
have been shown to cause direct activation of NK cells[52]. However, POWV directly infects macrophages(Fig. 2) at an early stage in the tick-feeding site [53, 54],
which potentially triggers the activation of NK and NKT
cells to produce IFNγ causing a cytotoxic response in
POWV virions (Fig. 2). The activation of cytotoxic T cells
followed by the secretion of perforin and granzyme B
could be another mechanism [55] for the cytotoxicity ofGottschalk et al. Infectious Agents and Cancer 2023, 18(1):7

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Fig. 2 POWV infection and innate immune response for the neuroinflammatory response. Powassan virus (POWV) directly infects Mφ at early onset
causing indirect activation of natural killer (NK), NKT, ­CD8+ T, and B cells. That infection triggers a protective innate immune response that results inthe production of IFNγ, IgM antibodies, and cytolytic proteins including perforin and granzyme B. These factors together cause cytotoxicity of POWV
particles (#1). Excessive production of IFNγ turns on the activation of microglial cells. Subsequent release of chemokines attracts inflammatory Th1
cells through the blood–brain barrier (BBB) and causes a demyelinating response in CNS (#2)

virus-infected cells (Fig. 2). However, acute infection followed by sustained activation of innate immune response
and IFNγ production could activate antigen-presenting
cells as well. The activations of macrophages, dendritic
cells, and microglia due to severe IFNγ production, could
switch on downstream cell-based adaptive inflammatory
response causing severe neuroinflammation (Fig. 2).
Similar to other tick-borne diseases such as Lyme disease, acute POWV illness presents with a diverse spectrum of clinical symptoms [56] including fever, pain,
headache, and muscle weakness. Treatment paradigms
are largely symptomatic and supportive thus contributing
to the unpredictable course of illness over time. Interestingly, one of the most common clinical manifestationsof POWV encephalitis is muscle fatigue. Encephalitis isoften associated with increased demyelination [57] of
peripheral nerves [58] that in turn causes impairment ofion conduction through sensory neurons [59] resulting inabnormalities in neuromuscular function [60].

Based on a recent statistical report of CDC [61], halfof the people who survive severe POWV encephalitis continue to suffer from long-term muscle weakness and fatigue following their acute infection phase.
Sometimes, a severe and chronic infection of POWV
can cause complete paralysis in one side of the body,described clinically as hemiplegia [61]. Complete ophthalmoplegia [61] with loss of eye muscle function
in both eyes is also common in POWV patients. A
detailed electroencephalogram (EEG) study indicatedthat severe demyelination of white matter in the temporal lobe that may contribute to the loss of downstream neuronal function controlling peripheral muscle
movement. Another literature reports significant infiltration of POWV in the ventral horn of the spinal
cord [62] that may also contribute to the demyelinating response in the peripheral nervous system and be apotential cause of severe weakness of peripheral muscle
tissue observed clinically. Taken together, these reports

Gottschalk et al. Infectious Agents and Cancer 2023, 18(1):7

suggest that muscle fatigue in POWV-infected patientsis possibly the result of a combination of factors including a severe demyelinating response in both the brain
and spinal cord, increased expression of IFNγ, the infiltration of inflammatory T cells through the BBB, andmicroglial activation.
Epstein–Barr virus (EBV) infection and muscle weakness

EBV is a DNA herpes virus that primarily spreads
through oral secretions and infects resident B lymphocytes (Fig. 3) in the oropharyngeal epithelium [63]. Upon
infection, EBV transforms B cells to B cell lymphoblastoid cells that eventually enter into the follicle, expands
to form a germinal center (GC) [64]. The host’s protective response becomes very active at that stage, which
elicits a cytotoxic response from NK cells, ­CD8+, andCD4 + T cells (Fig. 3). Infected memory B cells remainlatent during this stage. However, following a secondary
infection, these memory B cells rapidly convert to plasma
B cells. Although B cells are the primary target of EBV
infection, T cells can also be infected by EBV [65]. These

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lymphocytes can penetrate BBB [66] and engage withmicroglia (Fig. 3). In some cases, EBV directly infects
microglia [67]. Upon infection, extrachromosomal episomes of EBV [68], modulate the host immune responseby triggering the expression of a wide range of inflammatory cytokines such as IFN-γ, TNF-α, and IL-2 [69],
NF-κB [70], and proliferation of inflammatory T lymphocytes. Another possible mechanism of CNS inflammation
is molecular mimicry, by which homology between EBV
nuclear antigen-1 (EBNA-1) and host’s own myelin basic
protein (MBP) elicits the activation of autoreactive T
cells [71]. While most EBV infections are asymptomatic,
infections during adolescence and adulthood frequently
cause reactivation and mononucleosis [72]. Over 50% of
patients with infectious mononucleosis manifest the triadof fever, lymphadenopathy, and pharyngitis [73]. Other
symptoms include splenomegaly [74], hepatomegaly [75].
Leucocytosis, atypical lymphocytosis, and elevated liver
enzymes are also reported during EBV infection [76].
Recent studies demonstrate that muscle pain andfatigue can follow EBV infection and remain following

Fig. 3 EBV infection and inflammation. EBV engages in an interaction with B lymphocyte through its gp220/350 receptors to B cell surface
glycoprotein CD21. This interaction facilitates acute infection of EBV in B cells (#1), which subsequently causes transformation to B cell
lymphoblastoid cells. After that, these lymphoblastoid B cells undergo cytolysis (#2) by NK cells, C­ D8+, and ­CD4+ T cells. Some B cells escapethat cytolytic process and go to the latency (#3). During the late stage of life, virus reactivation (# 4) might occur followed by virus shedding, andsecondary infection to Th1 cells. These reactivated and infected B and T cells possibly enter to CNS through BBB, and potentially engage in a
microglial activation to induce inflammatory reactions (#5)

Gottschalk et al. Infectious Agents and Cancer 2023, 18(1):7

the resolution of other acute symptoms. According toWhite et al. [77], in a cohort of 108 subjects, a subset ofpatients with EBV-induced glandular fever having throat
and neck gland swelling was reported to display a distinct
physical and mental fatigue, excessive sleep, psychomotor retardation, poor concentration, and anhedonia. The
direct association of EBV infection and the pathogenesis of myalgic encephalomyelitis and chronic fatigue
syndrome (ME/CFS) has been reported anecdotally formany years, and more clearly following the identification of increased EBV induced gene 2 (EBI2) expression
in PBMC samples from a subgroup of ME/CFS patients[78].Moreover, upregulations of EBI2-associated early
growth response genes known as EGR1, EGR2, and EGR3
in PBMCs of ME/CFS patients further reinforced the
hypothesis that EBV infection could be directly linked
to long-term muscle fatigue and pain experienced by thepatient population [79]. In line with this idea, previous
studies using animal models demonstrated that physical stress-induced immobility and restraint, may cause
the upregulation of EGR1 and other immediate earlygenes in the CNS [80, 81]. Chronic EBV infection is often
reported in patients with polymyalgia rheumatica withperiodically disabling fatigue [82], and patients with primary fibromyalgia with progressive symptoms of fatigue[83]. According to a recent case study [84], EBV-infected­CD8+ cytotoxic T cells were found to have infiltrated in
the skeletal muscle tissue of 19 years old male sufferingfrom chronic and active EBV infection suggesting a directrole of EBV infection in cytotoxicity of skeletal muscle
tissue. In some patients, acute EBV infection also caused
severe myocardial necrosis with marked lymphocytic
infiltration [85] suggesting a direct role of EBV-infected
CD8 + T cells in acute cytotoxicity [86] of cardiac tissue[87]. Although, it is not yet completely understood how
EBV infection may be responsible for the developmentof long-term muscle fatigue, there exists clinical evidence for the development of other chronic illness [88]following acute of EBV infection including multiple sclerosis (MS) [89, 90] and, to some extent, systemic lupus
erythematosus (SLE) [91, 92]. Taken together, it is now
becoming evident that EBV infection and its subsequent
reactivation in humans can result in the potentiation of achronic inflammatory response in peripheral muscle tissue, and furthermore the infiltration of infected peripheral lymphocytes into the CNS.
These events eventually lead to the presentation of the
cardinal clinical symptoms of ME/CFS which include
fatigue, muscle weakness, dysautonomia and neurocognitive impairment. The potential relationship between
chronic EBV infection and MS-like encephalopathy was
further corroborated with a study by Jilek et al. [93], inwhich a patient with acute EBV infection was reported

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to display a severe myelin oligodendrocyte glycoprotein(MOG)-specific immune response accompanied withclinical signs of encephalopathy.
Collectively, muscle fatigue is a common clinical manifestation of EBV infection and reactivation and there
exist multiple potential molecular pathways that may
underlie clinical symptoms including the infiltration of
peripheral EBV-infected ­CD4+ T cells followed by reactive microgliosis, oligodendroglial demyelination, thedirect infiltration of CD8 + T cells and the subsequent
cytotoxic response that might cause the weakness in inskeletal muscle tissues (Fig. 3).
Human immunodeficiency virus (HIV) infection and muscle
weakness

Chronic HIV infection is often associated with severe
progressive neuromuscular weakness resulting in a
steady decline of muscle strength [94] and muscle mass[95], which can lead to the chronic movement impairment [96–98] and debilitating long-term disability. As amolecular mechanism, mitochondrial abnormality [99]has been often cited in muscle tissue of HIV patients.
Studies have identified HIV RNA in mitochondria of
mitochondria of muscle tissue collected from acute HIVinfected patients [100]. The HIV tat protein has beenshown to bind and alter mitochondrial membrane potential inducing mitochondrial death [101] and is a noteworthy molecular mechanism that may underlie the clinicalfeatures of severe fatigue and a loss of muscle tissue inthese patients. A specific interaction between the HIVviral protein R and the mitochondrial permeability transition pore complex (PTPC) has recently been demonstrated by Jacotot and colleagues [102]. In their work theyfound that PTPC-dependent permeabilization of mitochondrial membrane activates apoptosis and cytotoxicity [103] in muscle tissue. Apart from a mitochondrial
impairment, a chronic inflammatory response such asactivation of inflammatory T cells, gliosis, and demyelination are also critical factors [104–107] for the progression of neuromuscular weakness in HIV patients (Fig. 4).
HIV virions directly infect macrophages [108] andmicroglia [105] and upregulate the expressions of inflammatory cytokines such as IL-1β, IL6, and TNF-α [109];and chemokines such as CCL2, CCL5, and CXCL12 [110,111]. Expressions of other neurotoxic factors such as NO[112, 113] and ROS [114] are also stimulated throughthis pathway. These factors contribute to the apoptosis of oligodendrocytes, the primary myelinating cells in
CNS. Study suggests that the severity of myelin damage
and white matter abnormality is often positively correlated with the microglial activation [115]. Oligodendrocytes provide critical trophic support to the neuronalcells by covering axons with myelin membranes, which

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Fig. 4 Chronic HIV infection in neuroinflammation and demyelination. HIV directly infects CD4 + T lymphocytes (#1). Infected T cells interact withmacrophages causing the production of inflammatory cytokines (IL-1β, TNFα, IL6, and IL12), chemokines (CCL2. Rantes, CXCL12), reactive oxygen
species (ROS), and nitric oxide. These factors together contribute to the death of Schwan cells and therefore cause peripheral demyelination(#2). HIV virions and surface protein gp120 also contribute to CNS pathology by direct interaction with microglia (#3). Subsequent productionof inflammatory molecules directly causes the death of oligodendrocytes (#4) (abbreviated as “oligos”) followed by demyelination andneurodegenerationis crucially important for maintaining cellular functions
and electrical conduction [116]. Therefore, microglial
activation [117] followed by oligodendroglial injury [118]indirectly triggers neuronal damage in HIV patients [119,120].
In a direct mechanism, HIV surface protein gp120 has
been shown to interact with neurons [121] via the CXCR4
receptor. Upon interaction, gp120 stimulates the activation of NF-κB [122] in the neuron. GP120-mediated activation of NF-κB is reported to produce ROS [123] andstimulates the formation of rod-shaped actin-cofilin conjugated proteinopathic inclusions [121] causing neurodegeneration. In the peripheral nervous system, Schwan
cells also undergo apoptosis via similar mechanism. Theinteraction between CXCR4 of Schwan cells and gp120
of HIV causes exocytosis of lysosome and release of ATP[124]. Gp120 also triggers the release of TNFα uponbinding to CXCR4 on Schwan cells [125]. TNFα potentially stimulates TNFR1-mediated apoptosis in Schwan
cells and peripheral neurons causing neuropathy.

Long‑haul COVID and chronic fatigue

Based on our present research experience [126], dealing with the SARS-CoV2 virus in the laboratory is an
exceptionally challenging and unique experience whencompared to other similar RNA viruses. Potential mechanisms such as increased transmissibility [127], immune
escape [128], diagnostic failure [129], and reduced effectiveness of vaccines have resulted in the development ofnovel variants [130] that contain rather significant mutations all of its four protein domains spike (S), envelope(E), membrane (M) and nucleocapsid (N). Mutations inthese protein domains have been shown to alter an individual strain’s infectivity and transmissibility in the community. Perhaps most concerning are variants containing
mutations in the S protein and the variants subsequent
ability to evade approved vaccines and other treatment
modalities [131]. SARS-CoV2 employs a multilayered
mechanism to corrupt host cells (Fig. 5). These potential mechanisms include but are not limited to the binding with ACE-2 receptor followed by internalization inGottschalk et al. Infectious Agents and Cancer 2023, 18(1):7

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Fig. 5 Potential inflammatory pathways in muscle fatigue of long-haul COVID patients. Upon entry of SARS-CoV2, a possible cascade of acuteinflammatory pathways in the alveolar lumen was displayed. SARS-CoV2 employs its Spike protein or S-glycoprotein to bind with ACE2 receptor
and membrane-bound serine protease TMPRSS2. SARS-CoV2 also interacts with hyaluronan or hyaluronic acid of the glycocalyx layer. SEM (Spike,
Envelope, Membrane) pseudovirus particles or potential possible shedding of spike proteins also cause direct infection in alveolar dendritic cells
followed by MHC-II presentation and activation of CD4 + Th1 cells. Subsequent production of IFNγ and virus-induced activation of NF-κB might
evoke productions of inflammatory cytokines and chemokines commonly known as cytokine storm (#1). Th1 cell-mediated severe activation ofMφ and microglia might also cause non-specific phagocytosis of myelin (#2). Possible activation of B cells produces autoantibodies (#3). Eventually,
active virus particles, T cells, and inflammatory mediators spread through distant organs across BBB, and cause a cell-based inflammatory response
resulting demyelinating effects in the central and peripheral nervous system (#4). Impaired nerve signal causes muscular fatigue. B = B cells; T = T
cells; Abs = antibodies; APCs = antigen-presenting cells

the alveolar epithelium [132–134]; infection after active
engagement with transmembrane protease TMPRSS2[135, 136]; inflammation in endothelial glycocalyx followed by disruption of hyaluronic acid [137]; “shedding” of spike protein [138] followed by insertion to thehost membrane via exosomal vesicles spreading infection through spike (S), envelope (E) and membrane (M)protein enclosed pseudovirions [139]; a direct and rapidtranscription of viral proteins from its positive-strand
RNA; integration of gene material with host genome[140, 141] upon entry to the cells followed by exploiting host’s gene synthesis machinery [142]; taking overcellular metabolic processes of protein translation[143] and transport, and finally augmenting a “cytokine
storm” [144] via synthesis of inflammatory cytokines andchemokines (Fig. 5). COVID-19 displays complex andmultifaceted pathological outcomes corrupting almost
every organ of the human body. As a result, COVID-19
is not only a viral disease, but its pathological significancemight stretch to chronic inflammation [145–148], autoimmunity [149, 150], cancer [151], and neurodegeneration [152–154].

Although COVID-19 is significantly associated withdeath, 10% of total survivors display a chronic pathologythat includes fever, weakness, and muscle fatigue. These
symptoms are combinedly known as post-acute sequelae of COVID-19 (PASC); commonly referred to in theliterature and here as long-haul COVID patients (Longhaulers). “Long haulers” [155] are mostly PCR negative for COVID-19 [156], despite lingering symptoms.
Although the underlying mechanism is still unknown,
based on the history of viral inflammatory diseases, it
is expected that dysregulation of the adaptive immune
response [157, 158] could be one critical component ofdisease progression. Activation of C
­ D4+ Th1 cells upon
SARS-CoV2 infection and subsequent production ofanti-viral cytokine IFN-γ might be beneficial (25) for initial virus killing; however, prolonged activation of these
T cells might result in the development of a pathological inflammatory response (Fig. 5) including an elevatedproduction of chemokines and cytokines released activated macrophages and microglia. These soluble factors
recruit and engage Th1 cells on microglia followed by
microglial activation causing demyelination of neuronalGottschalk et al. Infectious Agents and Cancer 2023, 18(1):7

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fibers, sensory weakness, and potentially muscle fatigue.
In support of that possibility, SARS-CoV2 patients may
experience a “cytokine storm” characterized by upscaled
productions of inflammatory cytokines [159] such as IL2,
IL12, IFN-γ, IL6, and TNFα. Several case reports also
highlighted the potential demyelinating response [160–163] in SARS-CoV2 infected patients. A case study [160]revealed that a 54 year old SARS-CoV2 infected woman
was admitted to the hospital after seizure. An MRI scanrevealed multiple active demyelinating lesions in thebrain with numerous periventricular white matter abnormalities. Hyperintense white matter abnormalities werealso observed in the upper spinal cord. In another case[162], a 21-year-old post-COVID-19 patient, who met theclinical criteria for PASC and Long-haul COVID-19, wasadmitted following intermittent vomiting and malaise for4 days. A subsequent brain MRI revealed the presence ofbilateral posterior internal capsule lesions and longitudinally extensive transverse myelitis (LETM) in the upper
spinal cord. Combining the evidence showing an exaggerated production of inflammatory cytokines, the demyelinating response in the CNS, and the role of the impaired
adaptive immune response (Fig. 5) might explain theobserved symptoms of chronic muscle weakness, sensory
abnormalities, cognitive and autonomic dysfunction thatis observed in long haulers.
Although evidences to date suggest that SARS-CoV2
can mostly affect vascular and immune cells [164], few
in vitro cell culture studies also reported a direct neuroinvasive property of SARS-CoV2 in iPSC-derived neurons[165] and neural progenitor cells [166], which was further
substantiated by reports suggesting a direct SARS-CoV-2
infection in cortical neurons [167].
Another hypothesis underlying the pathogenesis ofLong haul COVID is a biochemical alteration of criticalmitochondrial metabolic pathways (Fig. 6). Similar toHIV, viral RNA transcripts of SARS-CoV2 were found[168] in host mitochondria and therefore, suggests

Fig. 6 Mitochondrial impairment and its potential involvement
in long-haul COVID. SARS-CoV2 directly infects mitochondria
via injecting its RNA, manipulates mitochondrial gene synthesis
machinery, and alters mitochondrial metabolomes. The impairment
can be the release of pro-apoptotic molecules such as Bax, Bad, andcytochrome C; reversal of membrane potential; downregulation of
β-oxidation and electron transport mechanism causing impaired
ATP synthesis; induction of mitochondria-independent cytosolic
glycolysis resulting in increased lactate synthesis. All these events
trigger mitochondrial loss and eventually fatigue

a direct role of SARS-CoV2 in in the modulation of
mitochondrial function. During the acute stage ofviral infection, SARS-CoV2 appears to hijack the host’s
mitochondrial machinery to favor mitochondrial ATP
synthesis and mitochondrial dynamics for its survival.
However, chronic, or long-term viral infection is known
to impair mitochondrial energy metabolism of ATP
synthesis; upregulate the synthesis and release of proapoptotic molecules such as Bax, Bad, and cytochrome

Table 1 Viral infections and potential mechanisms of chronic fatigue
Viral infection Immune cells infected and activated+ve

Potential mechanisms for fatigue
+ve

HHV6

CD4 (infection and apoptosis) and ­CD8
microglia (activation)

T cells, NK Cells,

Immunosuppression [18], autoimmune reaction (IgM abs), microglial activation and production of cytokines, Amyloid-beta [24],
OPC immuration, demyelination [169]

POWV

CD4+ve Th1 cells (proliferation), B Cell (activation), macrophage(infection and activation)

Proliferation of Th1 cells, IgM production, microglia-induced
inflammation, demyelination in peripheral nerves

EBV

B cells (infection), ­CD8+ve T cell activation, microglia (activation)

EBV-specific CD8 + ve T cell-induced Muscle cell apoptosis [85, 87]
Reactive gliosis [170], and demyelination [89]HIV

CD4+ve T cells (infection) [171], macrophages and microglia(infection)

Mitochondrial permeabilization and depolarization in muscle cells,
activation of inflammatory T cells, microgliosis, and demyelination

SARS-CoV2Lung endothelial cells (infection), kidney cells (infection), ­CD4+ve
T (infection) [172], ­CD8+ve T cells (activation and exhaustion)

Cytokine storm (IL-1b, TNF-1, IL6 etc.)[173], Glial activation [174],and T cells exhaustion. Mitochondrial impairment, Direct Infection
and toxicity to neurons

Gottschalk et al. Infectious Agents and Cancer 2023, 18(1):7

C; and augment ROS productions. Similarly, chronic
HCV infection impairs mitochondrial energy metabolism via inhibition of Complex I and V activity [175]and decreased fatty acid β-oxidation [176]. Prolonged
infection with HIV also induces mitochondrial depolarization, ROS production, and the activation of caspase 3 thus promoting accelerated mitochondrial death[177]. Chronic SARS-CoV2 infection also appears to
induce the alternative energy production pathways ofanaerobic glycolysis and the production of lactate [178],
and thereby, potentiating muscle fatigue (Fig. 6).
Neuroinflammation in ME/CFS

Although neuroinflammation is believed to play a critical role in the pathogenesis of ME/CFS, the molecularmechanism is still elusive. Human studies aimed toassess the contribution of inflammatory species in ME/
CFS are limited, mostly due to the difficulty in obtaining cerebrospinal fluid samples and a lack of appropriately powered non-invasive imagining studies invalidated cohorts [179]. Case–control studies assessing the cerebrospinal fluid collected from ME/CFS
patients compared to MS comparator samples indicate
a markedly disturbed pattern of CNS immune activation in ME/CFS patients with noted elevations of CCL1
(eotaxin) and an inverse relationship between interleukin 1 receptor antagonist and colony-stimulating factor 1, colony-stimulating factor 2 and interleukin 17F,
without effects on interleukin 1α or interleukin 1β. Furthermore, a study [180] assessed the CSF of ME/CFS
patients suggesting that CNS-specific immune dysregulation in ME/CFS patients could directly contribute to
the pathogenesis. This suggests a disturbance in interleukin 1 signaling [181–183]. Interestingly, multiple
studies assessing the cytokine expression patterns inperipheral blood of ME/CFS patients indicate a rather
consistent signature of proinflammatory cytokine activation and an overall T helper cell type 1 pattern associated with immune activation [184–189].
Based on our published literature [190], ME/CFS
serum evoked ROS and nitrite productions in cultured
microglial cells. Further molecular analyses revealed
that ME/CFS serum-induced production of ROS may be
due to the engagement of Receptor for advanced glycation end products or RAGE. Our study also highlighted
that ME/CFS patients might also demonstrate autophagy
impairment that causes serum upregulations of different
autophagy markers including ATG13 and alpha-synuclein. Alpha-synuclein is also known to induce microglial activation [191–193]. Both oligomeric [194] andS129P [195] alpha-synucleins induce neuroinflammatory

Page 11 of 16

events. Autophagy impairment directly causes mitochondrial metabolism and energy productions. Recent studies
also highlight the roles of CD4 + ve and CD8 + ve T cell
activation in the pathogenesis of ME/CFS [187]. Mandarano et al. have demonstrated that in ME/CFS patients,
both CD4 and CD8 + T cells have reduced glycolysis anddefective mitochondrial metabolism of energy.

Conclusion
In summary, viral infection is frequently associatedwith muscle weakness, fatigue, and degeneration. As
a molecular mechanism, alteration of adaptive immunity is widely accepted. Viruses such as EBV [196],
HHV6 [197], and HIV [198] directly infect CD4 + T
cells. These infected T cells proliferate and engage ina cross-talk with antigen-presenting cells (APCs) suchas dendritic cells, macrophage, NK cells, and microglia (Table 1). POWV directly infects macrophages.
That crosstalk stimulates the production of inflammatory cytokines, chemokine-driven recruitment ofinflammatory T cells in CNS, death of oligodendroglial
progenitor cells, oligodendroglial demyelination, neuronal dysfunction in the cerebellum and spinal cord
resulting in diminished synaptic transmission at theneuromuscular junction. Similar to CNS, demyelinating peripheral neuropathy is frequently observed inall viral diseases. Infected ­C D4+T cells display similar
inflammatory mechanisms of upregulated expressionsof cytokines, macrophage activation, death of Schwann
cells [199], demyelination of peripheral nerves, andmuscle fatigue.
In another hypothesis, virus-infected ­C D8+ cytotoxic T cells directly infiltrate muscle tissue causing
muscular degeneration, which is frequently observedin EBV and POWV infection. However, it is not known
if SARS-CoV2 directly infects ­C D4+ or ­C D8+ T cells.
However, SARS-CoV2 directly infects APCs such as
macrophage, dendritic cells, and microglia causing acell-based activation of C
­ D4+ and C­ d8+ T cells. Upon
activation, these inflammatory T cells potentially infiltrate into the CNS and augment a series of demyelinating responses including microglial activation, deathof OPCs, oligodendroglial demyelination, alterationof synaptic transmission that eventually led to muscle
weakness and fatigue. In addition to that, we also discussed a biochemical mechanism of mitochondrial
impairment and a chronic deficit of energy metabolism
in the pathogenesis of post-acute sequelae of COVID19. Taken together, our review article hypothesizes amechanistic insight of chronic muscle fatigue due tolong-term viral infection.

Gottschalk et al. Infectious Agents and Cancer 2023, 18(1):7

Page 12 of 16

Abbreviations
ME/CFS	Myalgic encephalomyelitis/chronic fatigue syndrome
PASC	Post-acute sequelae of COVID-19
EBV	Epstein–Barr virus
HHV6	Human herpesvirus 6HIV	Human immunodeficiency virus
Mφ	Macrophage
COVID-19	Coronavirus disease 2019NO	Nitric oxide
ROS	Reactive oxygen species

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Acknowledgements
This work was supported by Simmaron Research Inc., a non-profit 501C
research organization, Incline Village, NV 89451, as a result of funds from
Fondation Hesse Sibylla, Quebec, CA.
Author contributions
AR conceived the idea, designed review. GG and AR wrote the review article.
KK, DP, and GA provided inputs and proofread. All authors read and approved
the final manuscript.
Availability of data and materials
There is no electronic datasheet associated with this paper. No data in electronic repository.

6.

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Declarations

13.

Ethics approval and consent to participate
No part of this review article including images and texts had been publishedor reproduced before in any book, article, and other published literatures.
Images are original and not copied from any other sources.

14.

Consent for publication
All authors provided their consent to publish this review article.
Competing interests
AR, GG, JA, and DP are employee of Simmaron Research INC, a 501C non-profit
research organization. All authors declare no competing interests.
Author details
1
Simmaron Research INC, 948 Incline Way, Incline Village, NV 89451, USA.
2
Research and Development Laboratory, Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA.
3
Coppe Laboratories, W229N1870 Westwood Dr, Waukesha, WI 53186, USA.
Received: 6 November 2022 Accepted: 1 February 2023
Published: 7 February 2023

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