Potential Molecular Mechanisms Of Chronic Fatigue in Long Haul COVID And Other Viral Diseases Part 2
Oct 12, 2023
Long‑haul COVID and chronic fatigue
Cistanche can act as an anti-fatigue and stamina enhancer, and experimental studies have shown that the decoction of Cistanche tubulosa could effectively protect the liver hepatocytes and endothelial cells damaged in weight-bearing swimming mice, upregulate the expression of NOS3, and promote hepatic glycogen synthesis, thus exerting anti-fatigue efficacy. Phenylethanoid glycoside-rich Cistanche tubulosa extract could significantly reduce the serum creatine kinase, lactate dehydrogenase, and lactate levels, and increase the hemoglobin (HB) and glucose levels in ICR mice, and this could play an anti-fatigue role by decreasing the muscle damage and delaying the lactic acid enrichment for energy storage in mice. Compound Cistanche Tubulosa Tablets significantly prolonged the weight-bearing swimming time, increased the hepatic glycogen reserve, and decreased the serum urea level after exercise in mice, showing its anti-fatigue effect. The decoction of Cistanchis can improve endurance and accelerate the elimination of fatigue in exercising mice, and can also reduce the elevation of serum creatine kinase after load exercise and keep the ultrastructure of skeletal muscle of mice normal after exercise, which indicates that it has the effects of enhancing physical strength and anti-fatigue. Cistanchis also significantly prolonged the survival time of nitrite-poisoned mice and enhanced the tolerance against hypoxia and fatigue.
Click on tiredness
Why we will be tired? How can we solve the fatigue problems?
【Contact】Email: george.deng@wecistanche.com / WhatsApp:008613632399501/Wechat:13632399501
Based on our present research experience [126], dealing with the SARS-CoV-2 virus in the laboratory is an exceptionally challenging and unique experience when compared 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 of novel variants [130] that contain rather significant mutations in all of its four proteins domains spike (S), envelope (E), membrane (M) and nucleocapsid (N). Mutations in these 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 variant's 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 the alveolar epithelium [132–134]; infection after active engagement with transmembrane protease TMPRSS2 [135, 136]; infammation in endothelial glycocalyx followed by disruption of hyaluronic acid [137];“shedding” of spike protein [138] followed by insertion to the host membrane via exosomal vesicles spreading infection through spike (S), envelope (E) and membrane (M) protein enclosed pseudovirions [139]; a direct and rapid transcription 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 over cellular metabolic processes of protein translation [143] and transport, and fnally augmenting a “cytokine storm” [144] via synthesis of infammatory cytokines and chemokines (Fig. 5). COVID-19 displays complex and multifaceted pathological outcomes corrupting almost every organ of the human body. As a result, COVID-19 is not only a viral disease, but its pathological significance might stretch to chronic inflammation [145–148], autoimmunity [149, 150], cancer [151], and neurodegeneration [152–154].
Although COVID-19 is significantly associated with death, 10% of total survivors display a chronic pathology that includes fever, weakness, and muscle fatigue. These symptoms are combinedly known as post-acute sequelae of COVID-19 (PASC); commonly referred to in the literature and here as long-haul COVID patients (Long haulers). “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 of disease progression. Activation of CD4+ T1 cells upon SARS-CoV2 infection and subsequent production of anti-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 elevated production of chemokines and cytokines released activated macrophages and microglia. These soluble factors recruit and engage T1 cells on microglia followed by microglial activation causing demyelination of neuronal 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 a seizure. An MRI scan revealed multiple active demyelinating lesions in the brain with numerous periventricular white matter abnormalities. Hyperintense white matter abnormalities were also observed in the upper spinal cord. In another case [162], a 21-year-old post-COVID-19 patient, who met the clinical criteria for PASC and Long-haul COVID-19, was admitted following intermittent vomiting and malaise for 4 days. A subsequent brain MRI revealed the presence of bilateral 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 the observed symptoms of chronic muscle weakness, sensory abnormalities, cognitive and autonomic dysfunction that is observed in long haulers.
Although evidence to date suggests 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 of Long haul COVID is a biochemical alteration of critical mitochondrial metabolic pathways (Fig. 6). Similar to HIV, viral RNA transcripts of SARS-CoV2 were found [168] in host mitochondria and therefore, suggest a direct role of SARS-CoV2 in in the modulation of mitochondrial function. During the acute stage of viral 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 C; and augment ROS productions. Similarly, chronic HCV infection impairs mitochondrial energy metabolism via inhibition of Complex I and V activity [175] and decreases 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 of anaerobic glycolysis and the production of lactate [178], 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 molecular mechanism is still elusive. Human studies aimed to assess 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 imaging studies in validated 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 in the peripheral 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 Receptors 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] and S129P [195] alpha-synucleins induce neuroinflammatory events. Autophagy impairment directly causes mitochondrial metabolism and energy production. 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 and defective mitochondrial metabolism of energy.
Conclusion
In summary, viral infection is frequently associated with muscle weakness, fatigue, and degeneration. As a molecular mechanism, the 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 in a cross-talk with antigen-presenting cells (APCs) such as dendritic cells, macrophages, NK cells, and microglia (Table 1). POWV directly infects macrophages. Tat crosstalk stimulates the production of inflammatory cytokines, chemokine-driven recruitment of inflammatory 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 the neuromuscular junction. Similar to CNS, demyelinating peripheral neuropathy is frequently observed in all viral diseases. Infected CD4+T cells display similar inflammatory mechanisms of upregulated expressions of cytokines, macrophage activation, death of Schwann cells [199], demyelination of peripheral nerves, and muscle fatigue.
In another hypothesis, virus-infected CD8+ cytotoxic T cells directly infiltrate muscle tissue causing muscular degeneration, which is frequently observed in EBV and POWV infection. However, it is not known if SARS-CoV2 directly infects CD4+ or CD8+ T cells. However, SARS-CoV2 directly infects APCs such as macrophages, dendritic cells, and microglia causing a cell-based activation of CD4+ and Cd8+ T cells. Upon activation, these inflammatory T cells potentially infiltrate into the CNS and augment a series of demyelinating responses including microglial activation, death of OPCs, oligodendroglial demyelination, alteration of synaptic transmission that eventually leads 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 COVID-19. Taken together, our review article hypothesizes a mechanistic insight into chronic muscle fatigue due to long-term viral infection.
Abbreviations
ME/CFS Myalgic encephalomyelitis/chronic fatigue syndrome
PASC Post-acute sequelae of COVID-19
EBV Epstein–Barr virus
HHV6 Human herpesvirus 6
HIV Human immunodeficiency virus
Mφ Macrophage COVID-19 Coronavirus disease 2019
NO Nitric oxide
ROS Reactive oxygen species
Acknowledgments
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 and designed the 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 an electronic repository.
Declarations
Ethics approval and consent to participate
No part of this review article including images and texts had been published or reproduced before in any book, article, or other published literature. Images are original and not copied from any other sources.
Consent for publication
All authors provided their consent to publish this review article.
Competing interests
AR, GG, JA, and DP are employees of Simmaron Research INC, a 501C non-profit research organization. All authors declare no competing interests.
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