COVID-19 - A Redox Disease What a Stress Pandemic Can Teach Us About Resilience and What We May Learn from the Reactive Species Interactome About its Treatment.

Abstract

SIGNIFICANCE\nSARS-CoV-2, the virus causing COVID-19, affects every aspect of human life by challenging bodily, socio-economic and political systems at unprecedented levels. As vaccines become available, their distribution, safety and efficacy against emerging variants remain uncertain, and specific treatments are lacking. Recent Advances: Initially affecting the lungs, COVID-19 is a complex multi-systems disease that disturbs whole-body redox balance and can be long-lasting (Long-COVID). Numerous risk factors have been identified, but reasons for variations in susceptibility to infection, disease severity and outcome are poorly understood. The reactive species interactome (RSI) was recently introduced as a framework to conceptualise how cells and whole organisms sense, integrate and accommodate stress.\n\n\nCRITICAL ISSUES\nWe here consider COVID-19 as a redox disease, offering a holistic perspective of its effects on the human body, considering the vulnerability of complex interconnected systems with multi-organ/multi-level interdependencies. Host/viral glycan interactions underpin SARS-CoV-2 s extraordinary efficiency in gaining cellular access, crossing the epithelial/endothelial barrier to spread along the vascular/lymphatic endothelium, and evading antiviral/antioxidant defences. An inflammation-driven oxidative storm alters the redox landscape, eliciting epithelial, endothelial, mitochondrial, metabolic and immune dysfunction, and coagulopathy. Concomitantly reduced nitric oxide availability renders the sulfur-based redox circuitry vulnerable to oxidation, with eventual catastrophic failure in redox communication/regulation. Host nutrient limitations are crucial determinants of resilience at individual and population level.\n\n\nFUTURE DIRECTIONS\nWhile inflicting considerable damage to health and wellbeing, COVID-19 may provide the ultimate testing ground to improve diagnosis and treatment of redox-related stress diseases. Redox phenotyping of patients to characterise whole-body RSI status as the disease progresses may inform new therapeutic approaches to regain redox balance, reduce mortality in COVID-19 and other redox diseases, and provide opportunities to tackle Long-COVID.