processes Review Impact of Zinc, Glutathione, and Polyphenols as Antioxidants in the Immune Response against SARS-CoV-2 José Manuel Pérez de la Lastra 1,* , Celia Andrés-Juan 2, Francisco J. Plou 3 and Eduardo Pérez-Lebeña 4 1 Biotechnology of Macromolecules Research Group, Instituto de Productos Naturales y Agrobiología, IPNA-CSIC, 38206 San Cristóbal de la Laguna, Spain 2 Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, 47011 Valladolid, Spain; [email protected] 3 Instituto de Catálisis y Petroleoquímica, CSIC, 28049 Madrid, Spain; [email protected] 4 Sistemas de Biotecnología y Recursos Naturales, 47625 Valladolid, Spain; [email protected] * Correspondence: [email protected]; Tel.: +34-9222-60112 Abstract: SARS-CoV-2, the coronavirus triggering the disease COVID-19, has a catastrophic health and socioeconomic impact at a global scale. Three key factors contribute to the pathogenesis of COVID-19: excessive inflammation, immune system depression/inhibition, and a set of proinflamma- tory cytokines. Common to these factors, a central function of oxidative stress has been highlighted. A diversity of clinical trials focused predominantly on antioxidants are being implemented as potential therapies for COVID-19. In this study, we look at the role of zinc, glutathione, and polyphenols, as key antioxidants of possible medicinal or nutritional significance, and examine their role in the antiviral immune response induced by SARS-Cov-2. An unresolved question is why some people experience chronic COVID and others do not. Understanding the relationship between SARS-CoV-2 Citation: Pérez de la Lastra, J.M.; and the immune system, as well as the role of defective immune responses to disease development, Andrés-Juan, C.; Plou, F.J.; would be essential to recognize the pathogenesis of COVID-19, the risk factors that affect the harmful Pérez-Lebeña, E. Impact of Zinc, Glutathione, and Polyphenols as consequences of the disease, and the rational design of successful therapies and vaccinations. We Antioxidants in the Immune Response expect that our research will provide a novel perspective that contributes to the design of clinical or against SARS-CoV-2. Processes 2021, 9, nutritional targets for the prevention of this pandemic. 506. https://doi.org/10.3390/ pr9030506 Keywords: zinc; glutathione; polyphenols; flavonoids; ROS scavengers; immunity; SARS-COv-2; COVID-19 Academic Editor: Dionysios V. Chartoumpekis Received: 26 February 2021 1. Introduction Accepted: 8 March 2021 Molecular oxygen (O2) provides adenosine triphosphate (ATP) through its reduction Published: 11 March 2021 to H2O by mitochondrial respiration complexes of aerobic species. The by-products of cellular respiration are reactive oxygen species (ROS), comprised of free radical compounds, Publisher’s Note: MDPI stays neutral such as superoxide (O2−), hydroxyl radicals (HO·), lipid hydroperoxides, and reactive with regard to jurisdictional claims in non-radical compounds, such as hydrogen peroxide (H2O2), hypochlorous acid (HOCl), published maps and institutional affil- and ozone (O3). Under normal conditions, it is estimated that 2% of the oxygen consumed iations. by an aerobic cell diversifies towards the generation of reactive species. These reactive species carrying unpaired valence-shell electrons are fragile and, inside the cells, tend to capture electrons from other molecules in their vicinity, including DNA, lipids, and pro- teins. Such associations can inactivate target molecules irreversibly [1]. ROS development Copyright: © 2021 by the authors. in the mitochondria is the main source of ROS in mammalian cells. Reactive oxygen species Licensee MDPI, Basel, Switzerland. (ROS) catalysts include peroxidases, NADPH oxidase, nitric oxide synthase (NOX) iso- This article is an open access article forms, xanthine oxidase, lipoxygenases, glucose oxidase, and myeloperoxidase [2]. Low to distributed under the terms and intermediate levels of ROS have beneficial effects on many physiological mechanisms, such conditions of the Creative Commons as killing invading microorganisms, the wound healing process, and tissue regeneration [3]. Attribution (CC BY) license (https:// However, in high amounts, ROS can lead to cell death. Therefore, aerobic organisms have creativecommons.org/licenses/by/ evolved antioxidant machinery to regulate the amounts of various reactive ROS species 4.0/). Processes 2021, 9, 506. https://doi.org/10.3390/pr9030506 https://www.mdpi.com/journal/processes Processes 2021, 9, x FOR PEER REVIEW 2 of 17 Processes 2021, 9, 506 2 of 16 organisms have evolved antioxidant machinery to regulate the amounts of various reac- tive ROS species to prevent cellular damage. These antioxidant enzymes and molecules to prevent cellular damage. These antioxidant enzymes and molecules are designed to are designed to scavenge or prevent free radicals. ROS-scavenging enzymes include su- scavenge or prevent free radicals. ROS-scavenging enzymes include superoxide dismu- peroxidetase, glutathione dismutase, peroxidase, glutathione glutathione-reductase, peroxidase, glutathione-reductase, catalase, and superoxide catalase, reductase and super- [4]. oxideThese reductase enzymes [4]. are encodedThese enzymes by the are antioxidant encoded geneby the network antioxidant and gene are found network in virtually and are foundall organelles. in virtually all organelles. AsAs we we age, the rate of generation of reactive oxygen species by mitochondria, the mainmain source source of of their production, increases [5 [5]. The The increased production of these species inflictsinflicts injury injury to to the the inner inner membrane membrane of of th thee mitochondria, which by a positive feedback mechanismmechanism induces induces an an increase increase in in the the generation generation of ofreactive reactive species. species. As mitochondria As mitochondria are theare themost most important important source source of ofreactive reactive oxygen oxygen species, species, it itis is obvious obvious that that mitochondrial DNADNA is is more exposed than nuclear DNA to severe oxidative damage that can lead to mutationsmutations and and deletions deletions in in its its own own strand. strand. The The lower lower energy energy production production would affect cell function,function, and and on on the the other other hand, the the alteration in the electronic transport chain would increaseincrease the the rate rate of of generation generation of ofreactive reactive oxygen oxygen species. species. In this In ca thisse, case,the localized the localized alter- ationalteration would would be aggravated be aggravated by causing by causing subsequent subsequent damage damage to to mitochondrial mitochondrial DNA DNA [5,6]. [5,6]. ChangesChanges to to the the equilibrium of of ROS ROS production (Figure (Figure 11)) andand thethe potentialpotential toto sustainsustain aa highhigh degree degree of antioxidant antioxidant resistance resistance contribute contributess to oxidative stress. Therefore, cells have sophisticatedsophisticated DNA DNA repair repair systems. systems. Additionally, Additionally, they they are are related related to to the the decrease in the numbernumber of of mitochondria, mitochondria, a typical characteristic of aging cells [6]. [6]. The changes in the diet leadingleading to to a a reduction reduction in in the the generation generation of of reactive reactive oxygen oxygen species species by by the the mitochondria mitochondria is presentedpresented as one of the most most effective effective antioxid antioxidantsants means to ensure good health and even prolongprolong life [7]. [7]. FigureFigure 1. 1. SchematicSchematic reactions reactions leading leading to the to production the production of reactive of reactive oxygen oxygen speciesspecies (ROS) in (ROS) the in mitochondria.the mitochondria. TheThe immune immune system system must must function function very very rapidly rapidly and and accurately accurately to to remove remove SARS- SARS- CoV-2CoV-2 just over minutes after exposure, keep keepinging it from spreading and colonizing the lungslungs and and cardiovascular cardiovascular system. system. This This rapid rapid reaction reaction is is mediated by the innate immune system’ssystem’s natural natural killer killer (NK) (NK) cells cells [8]. [8]. Evidence suggests that that their dysfunction is related toto the the severity severity of of acute respiratory syndrome. In In the the most most vulnerable vulnerable populations populations (e.g., (e.g., elder,elder, obese, or overweight individuals), CO COVID-19VID-19 results results in in a cytokine storm and the productionproduction of of ROS. It is therefore imperative to gain in-depth knowledge of the critical activatorsactivators of of disease severity to minimize mortality and hospitalization rates that drive abnormalabnormal host host response. response. One One question question that that re remainsmains to to be answered is why some people suffer from chronic COVID-19 disease and others do not. This review examines the suffer from chronic COVID-19 disease and others do not. This review examines the role role of key antioxidants of possible medicinal or nutritional significance in the antiviral immune response induced by SARS-Cov-2. Particularly, we examine the antioxidants Processes 2021, 9, 506 3 of 16 zinc, glutathione, and polyphenols as determinants of the immune response triggered by SARS-Cov-2 [9]. 2. Virus-Induced Oxidative Damage Viruses