Centrality of G6PD in COVID-19: The Biochemical Rationale and Clinical Implications

Abstract

Introduction: COVID-19 is a novel and devastating disease. Its manifestations vary from asymptomatic to lethal. Moreover, mortality rates differ based on underlying health conditions and ethnicity. We investigated the biochemical rationale behind these observations using machine reasoning by the sci.AI system (https://sci.ai/). Facts were extracted and linked from publications available in nlm.nih.gov and Europe PMC to form the dataset which was validated by medical experts. Results: Based on the analysis of experimental and clinical data, we synthesized detailed biochemical pathways of COVID-19 pathogenesis which were used to explain epidemiological and clinical observations. Clinical manifestations and biomarkers are highlighted to monitor the course of COVID-19 and navigate treatment. As depicted in the Graphical Abstract, SARS-CoV-2 triggers a pro-oxidant (PO) response leading to the production of reactive oxygen species (ROS) as a normal innate defense. However, SARS-CoV-2's unique interference with the antioxidant (AO) system, through suppression of nitric oxide (NO) production in the renin-angiotensin-aldosterone system (RAAS), leads to an excessive inflammatory PO response. The excessive PO response becomes critical in cohorts with a compromised AO system such as patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd) where NO and glutathione (GSH) mechanisms are impaired. G6PDd develops in patients with metabolic syndrome. It is mediated by aldosterone (Ald) which also increases specifically in COVID-19. Conclusion: G6PD is essential for an adequate immune response. Both G6PDd and SARS-CoV-2 compromise the AO system through the same pathways rendering G6PDd the Achilles' heel for COVID-19. Thus, the evolutionary antimalarial advantage of the G6PDd cohort can be a disadvantage against SARS-CoV-2.

How Do Inflammatory Mediators, Immune Response and Air Pollution Contribute to COVID-19 Disease Severity? A Lesson to Learn

“…The production of reactive oxygen species (ROS) is part of the natural response to infections and is self-limited by anti-oxidant processes with a pivotal role for nitric oxide (NO) and glutathione (GSH). Production of these compounds is dependent on nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) produced principally by glucose-6-phosphate dehydrogenase (G6PD) [140]. Among the several hypotheses regarding predisposition to develop severe symptoms during COVID-19, G6PD deficit has been considered.…”

“…G6PD deficits can be acquired particularly in patients with metabolic syndrome [142]. Therefore, Buinitskaya et al [140] hypothesised that a G6PD deficit caused by metabolic syndrome could be responsible for decreased NO and GSH reducing the capacity to counteract SARS-CoV-2 and increasing multi-organ damage by reactive oxygen species (ROS).…”

“…Above, the role of primary factors of risk (clinical features: age, diabetes, cardiovascular diseases, and obesity [111][112][113][114]125,150]) for severe disease are shown. Below, other factors (biochemical features: levels of vitamin D, statins, interferon activity, and G6PD [132][133][134]138,140,145]) that are suggested to be involved in COVID-19 severity are summarised. Abbreviations: G6PD, glucose-6-phosphate dehydrogenase.…”

The Efficacy and Safety of Hydroxychloroquine in Patients with COVID-19: A Multicenter National Retrospective Cohort

“…G6PD deficiency has been reported to be disadvantageous against SARS-CoV-2 infections, as the virus prompts a pro-oxidant response while simultaneously suppressing the antioxidant system. Given that a G6PD deficiency results in a compromised antioxidant system, it is postulated that these individuals might suffer more severely from COVID-19 [ 34 ]. In addition, ex vivo studies show increased vulnerability of G6PD-deficient cells to SARS-CoV-2 infection than G6PD normal cells [ 35 ].…”

Therapeutic Intervention of COVID-19 by Natural Products: A Population-Specific Survey Directed Approach

“…In the past, an ex vivo study has shown that G6PDd cells are more vulnerable to human coronavirus infection than G6PD-normal cells [ 97 ], which should have made researchers interested in examining the association between G6PDd and COVID-19 [ 111 ]. Buinitskaya et al (2020) from their recent review study, reported that G6PDd and SARS-CoV-2 both compromise the anti-inflammatory antioxidant system through the same pathways [ 112 ]. In this sense, overproduction of ROS and excess oxidative damage leading to impaired immune responses, over exuberant cytokine storm, and pulmonary dysfunction in response to the COVID-19 won’t be adequately fenced in those with inherited G6PDd.…”