Pathological Aspects of COVID-19 as a Conformational Disease and the Use of Pharmacological Chaperones as a Potential Therapeutic Strategy

Abstract

Coronavirus disease 2019 (COVID-19), the seventh human coronavirus infectious disease, was first reported in Wuhan, China, in December 2019, followed by its rapid spread globally (251,059 deaths, on May 5, 2020, by Johns Hopkins University). An early clinical report showed that fever, cough, fatigue, sputum production, and myalgia were initial symptoms, with the development of pneumonia as the disease progressed. Increases in the level of serum liver enzymes, D-dimer, cardiac troponin I, and creatinine have been observed in severely ill patients, indicating that multiple organ failure had occurred in these cases. Lymphopenia and an increase in interleukin-6 (IL-6) were also observed. Although COVID-19 patients are administered glucocorticoid therapy to treat the excessive immune response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, the efficacy of this form of therapy is unclear. Viremia is observed in severe cases, suggesting that in addition to type II alveolar epithelial cells, many cell types, such as vascular endothelial cells, cardiomyocytes, renal tubular cells, neuronal cells, and lymphocytes, may be damaged. The improvement of survival rates requires elucidation of the mechanism by which cellular damage occurs during viral infection. Cellular therapy, along with organ support systems such as oxygen therapy, artificial ventilation, extra corporeal membrane oxygenation and dialysis, as well as antiviral therapy, are required. Viral replication in infected host cells may perturb protein folding in the endoplasmic reticulum (ER), causing ER stress. Although an adaptive cellular response, i.e. the unfolded protein response, can compensate for the misfolded protein burden to some extent, continued viral proliferation may induce inflammation and cell death. Therefore, we propose that proteostasis dysfunction may cause conformational disorders in COVID-19. The application of pharmacological chaperone therapy to treat COVID-19 patients is additionally discussed.

Molecular and Cellular Effects of Chemical Chaperone—TUDCA on ER-Stressed NHAC-kn Human Articular Chondrocytes Cultured in Normoxic and Hypoxic Conditions

“…This may suggest the existence of other pro-apoptotic pathways activated in addition to ER stress after exposition to TNC. Indeed, overproduction of ROS has been already demonstrated to contribute to apoptosis of cardiomyocytes and cardiomyoblasts after TNC treatment [48,49]. In our study we also found a small but significant increase in ROS generation in TNC-treated cells, which was not affected by TUDCA supplementation.…”

Pathophysiological Clues to How the Emergent SARS-CoV-2 Can Potentially Increase the Susceptibility to Neurodegeneration

“…Furthermore, SARS-CoV proteins, ORF-3a, ORF-3b, ORF-6, ORF-7a, can induce apoptosis of host cells, which is mediated by caspase-3 and ER stress and Janus Kinase (JNK) pathways [113]. Although such evidence is not available for SARS-CoV-2 yet, but the structural and mechanistic behavior similarity of these viruses makes these assumptions so likely that targeting ER stress has been suggested as a treatment for SARS-CoV-2 [114,115]. Thus, it is possible that COVID-19 infection, enters the neurons, by hijacking protein machinery disrupts ER and mitochondrial function and upregulates accumulation of misfolded proteins, thereby triggers mitochondrial oxidative stress and contributes to apoptosis and degeneration of neurons [55,60,116].…”

Effects of Cell Proteostasis Network on the Survival of SARS-CoV-2

“…Molecular chaperones, such as GRP78 and GRP94, BiP (binding immunoglobulin protein), PDI (protein disulfide isomerase), calreticulin, and calnexin participate in the folding of SARS-CoV-2 proteins, to ensure proper folding, sugar chain modification, and complex formation [ 38 , 39 ]. BiP chaperones are attached to the ATF6 (activated transcription factor 6), IRE1 (inositol requiring kinase-1), and PERK (PKR-like ER related kinase) [ 29 , 40 ]. The chaperone, also counteract the effect of the stress of the host cell caused by viral infection.…”

“…Due to the possible role of chaperones in the survival and infection of SARS-CoV-2, today chaperone therapy has attracted the attention of researchers to treat COVID-19 disease. Drug chaperones have been suggested to suppress cell dysfunction, inflammation, and apoptosis by preventing the accumulation of unfold proteins in ER and reducing ER stress, and have been proposed as a promising therapeutic strategy in COVID-19 [ 40 ]. However, this method of treatment is debatable.…”

“…The mentioned mechanism includes the suppression of BiP dissociation from PERK, and inhibition of eIF2α phosphorylation, and ATF4-CHOP activation. Reduced ATF4-CHOP increases the expression of anti-apoptotic BCL-2 and decreases the expression of pro-apoptotic Bax, and then suppression of caspase-3 [ 40 ]. The role of the drug chaperon of TUDCA against some acute diseases has been studied in cell cultures and animal models [ 74 – 76 ].…”