The age-dependent decline of the extracellular thiol-disulfide balance and its role in SARS-CoV-2 infection

Abstract

SARS-CoV-2 (COVID-19) infection can cause a severe respiratory distress syndrome. The risk of severe manifestations and mortality characteristically increase in the elderly and in the presence of non-COVID-19 comorbidity. We and others previously demonstrated that the low molecular weight (LMW) and protein thiol/disulfide ratio declines in human plasma with age and such decline is even more rapid in the case of inflammatory and premature aging diseases, which are also associated with the most severe complications of COVID-19 infection. The same decline with age of the LMW thiol/disulfide ratio observed in plasma appears to occur in the extracellular fluids of the respiratory tract and in association with many pulmonary diseases that characteristically reduce the concentrations and adaptive stress response of the lung glutathione. Early evidence in literature suggests that the thiol to disulfide balance of critical Cys residues of the COVID-19 spike protein and the ACE-2 receptor may influence the risk of infection and the severity of the disease, with a more oxidizing environment producing the worst prognosis. With this hypothesis paper we propose that the age-dependent decline of LMW thiol/disulfide ratio of the extracellular fluids, could play a role in promoting the physical (protein-protein) interaction of CoV-2 and the host cell in the airways. Therefore, this redox-dependent interaction is expected to affect the risk of severe infection in an age-dependent manner. The hypothesis can be verified in experimental models of in vitro CoV-2 infection and at the clinical level in that LMW thiols and protein thiolation can now be investigated with standardized, reliable and versatile laboratory protocols. Presenting the verification strategy of our hypothesis, we also discuss available nutritional and ancillary pharmacological strategies to intervene on the thiol/disulfide ratio of extracellular fluids of subjects at risk of infection and COVID-19 patients.

Keywords: ACE-2 receptor; Aging; COVID-19; Cysteine; Glutathione; Inflammation; Low molecular mass thiols; Lung diseases; Oxidative stress; Protein thiols; S-thiolation; SARS-CoV-2; Spike S protein.

Graphical abstract

Fig. 1

Schematic representation of the contact zone between SARS-CoV-2 spike receptor-binding domain (orange) and ACE2 (green). Disulfide bridges critical for binding affinity are present at position C480–C488 and C344–C361 (shown on the left); their reduction at the protein-protein interface is proposed to produce conformational changes that decrease binding affinity [17,18]. The figure was drawn using PDB entry 6M0J. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Age-dependence of thiol/disulfide ratios in plasma. Panel A: Age vs GSH/GSSG, r = −0.5, two-tailed p values < 0.001; panel B: Age vs cysteine/cystine, r = −0.315, two-tailed p values < 0.01 panel C: Age vs cysteinylglycine/cystinylglycine, r = −0.708, two-tailed p values < 0.0001; panel D: Age vs PTI, r = 0.686, two-tailed p values < 0.0001. Data from Refs. [22] (red symbols), [58] (green), [61] (blue), [62] (pink). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

(Graphical Abstract) The Protein Thiolation Index (PTI), an indicator of the thiol/disulfide balance of extracellular fluids, increases its levels with age, thus mirroring the decline of redox homeostasis systems of tissues. In this study we propose that PTI and extracellular thiol analysis can be utilized to predict the risk of more severe infections and clinical manifestations by higher oxidation of interaction domain Cys that are critical for CoV-2 spike protein and ACE-2 receptor binding. Pro-oxidant conditions of the extracellular environment have been described to promote the physical (protein-protein) interaction of viral proteins and host cell receptors in many other viruses [[16], [19]], thus representing an age-dependent molecular process of increased susceptibility to viral infections and their complications.