Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases

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 a majority of infected patients survive after mild to moderate reactions after two to six weeks, a growing population of patients suffers for months with severe and prolonged symptoms of fatigue, depression, and anxiety. These patients are 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 the molecular 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 with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Keywords: CD4+ and CD8+ T cells; IFNγ; Microglia; Mitochondria.

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 the immune tolerance response (#3). IL10 and IL4 are also secreted from Th2 cells during activation of FOXP3^+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 of oligos, 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

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 in the 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)

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, CD8⁺, and CD4⁺ T cells. Some B cells escape that cytolytic process and go to the latency (#3). During the late stage of life, virus reactivation (# 4) might occur followed by virus shedding, and secondary 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)

Fig. 4

Chronic HIV infection in neuroinflammation and demyelination. HIV directly infects CD4 ⁺ T lymphocytes (#1). Infected T cells interact with macrophages 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 production of inflammatory molecules directly causes the death of oligodendrocytes (#4) (abbreviated as “oligos”) followed by demyelination and neurodegeneration

Fig. 5

Potential inflammatory pathways in muscle fatigue of long-haul COVID patients. Upon entry of SARS-CoV2, a possible cascade of acute inflammatory 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 of Mφ 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

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, and cytochrome 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