Do free radical NETwork and oxidative stress disparities in African Americans enhance their vulnerability to SARS-CoV-2 infection and COVID-19 severity?

Abstract

This review focuses on the hypothetical mechanisms for enhanced vulnerability of African Americans to SARS-CoV-2 infection, COVID-19 severity, and increased deaths. A disproportionately higher number of African Americans are afflicted with autoimmune and inflammatory diseases (e.g., diabetes, hypertension, obesity), and SARS-CoV-2 has helped expose these health disparities. Several factors including socioeconomic status, inferior health care, and work circumstances contribute to these disparities. Identifying potential inflammatory biomarkers and decreasing basal levels in high-risk individuals with comorbidities through preventive measures is critical. Immune cells, particularly neutrophils, protect us against pathogens (bacteria, fungi, and viruses) through increased generation of free radicals or oxidants and neutrophil extracellular traps (NETs) that ensnare pathogens, killing them extracellularly. However, continued generation of NETs coupled with the lack of prompt removal pose danger to host cells. NET levels are increased during pro-inflammatory diseases. COVID-19 patients exhibit elevated NET levels, depending upon disease severity. Conceivably, high-risk individuals with elevated basal NET levels would exhibit hyper-inflammation when infected with SARS-CoV-2, amplifying disease severity and deaths. Drugs inhibiting oxidant formation and vitamin supplements decreased NET formation in mice models of inflammation. Thus, it is conceivable that preventive treatments lowering NET levels and inflammation in high-risk individuals could mitigate SARS-CoV-2-induced complications and decrease mortality.

Keywords: African Americans; Black Americans; COVID-19; Coronavirus; Neutrophils; Oxidants.

Graphical abstract

Fig. 1

Conventional host defense involving the stimulation of oxidative or respiratory burst in neutrophils during phagocytosis of pathogens, including bacteria, fungi, or viruses. Activation of the enzyme, NADPH oxidase, stimulates O₂^•– and H₂O₂ formation. Degranulation releases the enzyme MPO that in the presence of H₂O₂ oxidizes the chloride anion to HOCl or bleach, a strong antimicrobial agent. Reprinted from Redox Biology, 1, Kalyanaraman B, Teaching the basics of redox biology to medical and graduate students: Oxidants, antioxidants and disease mechanisms, 244–257, Copyright 2013, with permission from Elsevier.

Fig. 2

Oxidants cascading from one-electron reduction of oxygen to O₂^•–. Several potent oxidants are generated from H₂O₂ formed from dismutation of O₂^•–. One of the most potent antimicrobial oxidants, HOCl, is formed from MPO-catalyzed oxidation of chloride ion. ONOO⁻, another potent oxidant, is formed from the reaction between O₂^•– and nitric oxide and results in the oxidation of lipid, proteins, and DNA.

Fig. 3

NETosis and NET formation as an extracellular antimicrobial mechanism. Stimulation of oxidants during the phagocytic killing of microbes causes rupture of nuclear membranes extruding chromatin, MPO, neutrophil elastase, histones, and proteolytic enzymes into the extracellular space forming a net-like structure that traps and kills pathogens.

Fig. 4

SARS-CoV-2 from the respiratory tract enters lung cells through the ACE2 receptor. The virus inactivates the ability of ACE2 to convert AT-II to AT-1,-7. SARS-CoV-2 stimulates PMN (polymorphonuclear neutrophils-mediated) O₂^•–.

Fig. 5

Potential thrombolytic effect of NAC. Increased formation of O₂^•– as shown in Fig. 4 results in enhanced VWF and thrombosis. Reduction of disulfide (-S-S-) to sulfhydryl groups (-SH) in VWF cross linked to proteins is proposed as the likely mechanism for the vasoprotective effects of NAC.

Fig. 6

Structures of drugs that target mitochondria and inhibit Nox2 activity.