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Review
. 2022 Jan 28;127(2):214-232.
doi: 10.1017/S0007114521000738. Epub 2021 Mar 1.

Zinc deficiency as a possible risk factor for increased susceptibility and severe progression of Corona Virus Disease 19

Inga Wessels  1 , Benjamin Rolles  2 , Alan J Slusarenko  3 , Lothar Rink  1
Affiliations
Review

Zinc deficiency as a possible risk factor for increased susceptibility and severe progression of Corona Virus Disease 19

Inga Wessels et al. Br J Nutr. .

Abstract

The importance of Zn for human health becomes obvious during Zn deficiency. Even mild insufficiencies of Zn cause alterations in haematopoiesis and immune functions, resulting in a proinflammatory phenotype and a disturbed redox metabolism. Although immune system malfunction has the most obvious effect, the functions of several tissue cell types are disturbed if Zn supply is limiting. Adhesion molecules and tight junction proteins decrease, while cell death increases, generating barrier dysfunction and possibly organ failure. Taken together, Zn deficiency both weakens the resistance of the human body towards pathogens and at the same time increases the danger of an overactive immune response that may cause tissue damage. The case numbers of Corona Virus Disease 19 (COVID-19) are still increasing, which is causing enormous problems for health systems and economies. There is an urgent need to reduce both the number of severe cases and the resulting deaths. While therapeutic options are still under investigation, and first vaccines have been approved, cost-effective ways to reduce the likelihood of or even prevent infection, and the transition from mild symptoms to more serious detrimental disease, are highly desirable. Nutritional supplementation might be an effective option to achieve these aims. In this review, we discuss known Zn deficiency effects in the context of an infection with Severe Acute Respiratory Syndrome-Coronavirus-2 and its currently known pathogenic mechanisms and elaborate on how severe pre-existing Zn deficiency may pre-dispose patients to a severe progression of COVID-19. First published clinical data on the association of Zn homoeostasis with COVID-19 and registered studies in progress are listed.

Keywords: Corona Virus Disease 19; Impaired immune system; Severe Acute Respiratory Syndrome-Coronavirus-2; Zinc deficiency.

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Figures

Fig. 1
Fig. 1
Summary of complications that can be expected in patients with pre-existing zinc deficiency, when challenged by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). A patient with no co-morbidities and a balanced zinc homoeostasis will most likely develop no or mild symptoms or complications if infected with SARS-CoV-2 because immune cell numbers and functions are balanced, as are the other parameters listed in the Figure. However, zinc deficiency alone will result in the alterations indicated in the Figure. Preconditions resulting from zinc deficiency may result in the development of severe symptoms, critical illness and even death if the patient becomes infected with SARS-CoV-2. ARDS, acute respiratory distress syndrome; CNS, central nervous system; IFN, interferon; MMP, matrix metalloproteinase; TH, T helper cell; Treg, regulatory T cell; ZA, zinc adequate; ZD: zinc deficient.
Fig. 2
Fig. 2
Alterations in haematopoiesis are reported during zinc deficiency as well as in Corona Virus Disease 19 (COVID-19). During zinc deficiency, indicated by the red arrow, differentiation of myeloid cells, including polymorphonuclear neutrophils (PMN) and monocytes (Mo), is prioritised over development of adaptive immune cells, this especially impacts T cells (T). Amongst others, the prioritisation of myeloid cells may be explained by changes in growth factor expression: granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte-colony-stimulating factor (G-CSF) were described to be highly expressed, while levels of IL-2 are decreased during zinc deficiency. Furthermore, the T helper cell (TH)1:TH2 ratio is imbalanced during zinc deficiency, Th17 cell numbers are increased, while regulatory T cell (Treg) numbers were described as decreased as well as their functions. Most of those haematopoietic disturbances found during zinc deficiency are generally described for COVID-19 patients, as detailed in the text. B, B cell; BCP, B-cell progenitor; E, erythrocyte; EPO, erythropoietin; GM, granulocyte-macrophage progenitor; HSC, hematopoietic stem cell; MEP, megakaryocyte–erythroid progenitor; NK, natural killer cell; Pl, platelets; SCF, stem cell factor; TC: cytotoxic T cell; TNK, T and NK cell progenitor; TPO, Thrombopoietin.
Fig. 3
Fig. 3
Pulmonary effects observed in Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infected patients with pre-existing zinc deficiency as compared with patients with a balanced zinc homoeostasis. Pre-existing zinc deficiency (left) was suggested to increase the number, recruitment and inflammatory potential of especially PMN to the insides of the bronchi. Lymphocyte numbers are generally decreased, most prominently affecting T helper cell (TH) cells. The zinc deficiency-related decrease in tight junction expression and the increase in endothelial cell apoptosis have several consequences. Thus, infiltration of the lung by host cells, as well as the leakage of pathogens such as SARS-CoV-2 and secondary pathogens such as Streptococcus pneumoniae into the vascular system, is frequently observed during zinc deficiency. Detailed explanations can be found in the text. For comparison, the characteristics of zinc-adequate individual are indicated on the right. Ab, antibody; B, B cell; E, erythrocyte; G-CSF, granulocyte colony-stimulating factor; GC, glucocorticoid; GM-CSF, granulocyte-macrophage CSF; MMP, matrix metalloproteinase; Mo, monocyte; Mϕ, macrophage; NET, neutrophil extracellular trap; NK, natural killer cell; Pl, platelet; PMN, polymorphonuclear neutrophil; ROS, reactive oxygen species; Tc, cytotoxic T cell; TJ, tight junction; ZA, zinc adequate; ZD, zinc deficient.
Fig. 4
Fig. 4
Effects of zinc deficiency on stress-induced changes in redox metabolism. Green arrows indicate zinc-dependent cellular functions. Red arrows illustrate the effects of zinc deficiency. A detailed description of the mechanisms underlying disturbed redox metabolism during zinc deficiency can be found in the text. AP-1, Activator protein 1; Bcl-2, B-cell lymphoma 2; CAT, catalase; COX, Cyclo-oxygenase; CRP, C-reactive protein; ER, endoplasmic reticulum; GPx, glutathione peroxidase; ICAM, intercellular adhesion molecule-1; iNOS, inducible nitric oxide synthase; MT, metallothionein; MTF, metal-responsive transcription factor-1; Ox, oxidated; MCP, monocyte chemoattractant protein; NIK, NFκB-Inducing Kinase; ROS, reactive oxygen species; SOD, superoxide dismutase; VCAM, vascular cell adhesion molecule.
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References

    1. World Health Organization (2020) WHO Director-General’s opening remarks at the media briefing on COVID-19–11 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-re... (accessed July 2020).
    1. World Health Organization (2020) Clinical Management of COVID-19 Interim Guidance 27 May 2020, 2019th ed. Geneva: WHO.
    1. Bencivenga L, Rengo G & Varricchi G (2020) Elderly at time of Coronavirus disease 2019 (COVID-19): possible role of immunosenescence and malnutrition. Geroscience 42, 1089–1092. - PMC - PubMed
    1. World Health Organization (2020) Malnutrition. https://www.who.int/news-room/fact-sheets/detail/malnutrition (accessed July 2020).
    1. Rios-Lugo MJ, Madrigal-Arellano C, Gaytán-Hernández D, et al. (2020) Association of serum zinc levels in overweight and obesity. Biol Trace Elem Res 198, 51–57. - PubMed
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