Can iron, zinc, copper and selenium status be a prognostic determinant in COVID-19 patients?

Abstract

In severe COVID-19, the levels of iron (Fe), copper (Cu), zinc (Zn) and selenium (Se), do not only regulate host immune responses, but modify the viral genome, as well. While low serum Fe concentration is an independent risk factor for the increased death rate, Zn controls oxidative stress, synthesis of inflammatory cytokines and viral replication. Therefore, Zn deficiency associates with a worse prognosis. Although Cu exposure inactivates the viral genome and exhibits spike protein dispersal, increase in Cu/Zn due to high serum Cu levels, are correlated with enhanced risk of infections. Se levels are significantly higher in surviving COVID-19 patients. Meanwhile, both Zn and Se suppress the replication of SARS-CoV-2. Since the balance between the deficiency and oversupply of these metals due to a reciprocal relationship, has decisive effect on the prognosis of the SARS-CoV-2 infection, monitoring their concentrations may facilitate improved outcomes for patients suffering from COVID-19.

Keywords: Copper; Iron; Oxidative stress; SARS-CoV-2; Selenium; Zinc.

Fig. 1

SARS-CoV-2 binds to ACE2 receptors on the respiratory epithelium and infiltrating macrophages, leads to activation of the inducible transcription factor, NF-κB. Subsequently, it induces “cytokine storm” and eventually provokes ARDS. Labile iron in the cell that promotes MAS is characterized by cytokine storm and contributes to the formation of ROS. In PI3K-Akt-mTOR pathway nuclear translocation of IRF7 leads to transcriptional activation of type I interferon (IFN) genes. The key component of mTORC2, Rictor regulates IFN-α production. The produced IFN-α binds to IFN-α receptors (IFNAR1-IFNAR2) and provides immune protection against SARS-CoV-2. Zn, Cu and Se target multiple pathways to hamper the functional and structural consequences of inflammatory response caused by SARS-CoV-2 and inactivates the viral genomes of SARS-CoV-2 and exhibits irreversible effects on virus morphology. Thus, envelope disintegration and dispersal of spike protein occurs. Zinc and Se on the one hand suppress the life cycle of SARS-CoV-2 by inhibiting Mpro and PLpro of SARS-CoV-2, on the other hand strengthen the immune defense and counteract to the complications of SARS-CoV-2 infection (Abbreviations. ACE2: the cell receptor angiotensin-converting enzyme II; AKT: protein kinase B; AngII: angiotensin II; ARDS: acute respiratory distress syndrome; AT1R: angiotensin II receptor type 1; CHOP: CCAAT/enhancer-binding protein (C/EBP)-homologous protein; CoVS1: SARS-CoV-2 Spike protein; Cu: copper; ER: endoplasmic reticulum; Fe: iron; FoxP3: the transcription factor forkhead box P3; HAT: CD25 + hyperactivated T-cells; IFNAR: IFN α receptor; IFNα: (type-1 interferon) interferon alpha; IKKβ: IκB kinase β; IL-6: interleukin-6; IRE1: inositol-requiring enzyme 1; IRF7: interferon regulatory factor 7; ISG: interferon-stimulated gene; JAK: janus kinase; JNK: c-Jun N-terminal kinase; KLF: Krüppel-like transcription factor; MAPK: p38-mitogen-activated protein kinases; MAS: macrophage activation syndrome; Mpro: a key enzyme of SARS-CoV-2 and has a pivotal role in mediating viral replication and transcription; mTORC1: mammalian target of rapamycin complex 1; mTORC2: mammalian target of rapamycin complex 2; NFκB: nuclear factor-κB; NOX: nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; p: phosphorylation; PERK: protein kinase r-like endoplasmic reticulum kinase; PI3K: phosphoinositide 3-kinase; PLpro: papain-like protease of SARS-CoV-2; RdRp: RNA dependent RNA polymerase; Rictor: The rictor-mTOR complex directly phosphorylated AKT; ROS: reactive oxygen species; S6K1: s6 kinase 1; Se: selenium; STAT: signal transducers and activators of transcription; TMPRSS2: the serine protease of SARS-CoV receptor ACE2 in S protein priming for entry to target cell; UPR: unfolded protein response; Zn: zinc).