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. 2022 Dec 20;24(1):15.
doi: 10.3390/ijms24010015.

Iron Dyshomeostasis in COVID-19: Biomarkers Reveal a Functional Link to 5-Lipoxygenase Activation

Beatrice Dufrusine  1   2   3 , Silvia Valentinuzzi  3   4 , Sandra Bibbò  2   3 , Verena Damiani  2   3 , Paola Lanuti  3   5 , Damiana Pieragostino  2   3 , Piero Del Boccio  3   4 , Ersilia D'Alessandro  3 , Alberto Rabottini  3 , Alessandro Berghella  1 , Nerino Allocati  2 , Katia Falasca  5   6 , Claudio Ucciferri  6 , Francesco Mucedola  6 , Marco Di Perna  7 , Laura Martino  7 , Jacopo Vecchiet  5   6 , Vincenzo De Laurenzi  2   3 , Enrico Dainese  1
Affiliations

Iron Dyshomeostasis in COVID-19: Biomarkers Reveal a Functional Link to 5-Lipoxygenase Activation

Beatrice Dufrusine et al. Int J Mol Sci. .

Abstract

Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical symptoms. After acute infection, some subjects develop a post-COVID-19 syndrome known as long-COVID. This study aims to recognize the molecular and functional mechanisms that occur in COVID-19 and long-COVID patients and identify useful biomarkers for the management of patients with COVID-19 and long-COVID. Here, we profiled the response to COVID-19 by performing a proteomic analysis of lymphocytes isolated from patients. We identified significant changes in proteins involved in iron metabolism using different biochemical analyses, considering ceruloplasmin (Cp), transferrin (Tf), hemopexin (HPX), lipocalin 2 (LCN2), and superoxide dismutase 1 (SOD1). Moreover, our results show an activation of 5-lipoxygenase (5-LOX) in COVID-19 and in long-COVID possibly through an iron-dependent post-translational mechanism. Furthermore, this work defines leukotriene B4 (LTB4) and lipocalin 2 (LCN2) as possible markers of COVID-19 and long-COVID and suggests novel opportunities for prevention and treatment.

Keywords: 5-lipoxygenase; COVID-19; iron metabolism; leukotriene B4; lipocalin 2; long-COVID.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Characterization of proteome lymphocyte measurements taken from COVID-19 patients. Qualitative STRING networks from gene ontology analysis of the iron-related metabolism proteins quantified in CD3+ and CD19+ sorted lymphocytes. The numbers beside each protein represent the ratio between the protein abundance in COVID-19 patients and controls and are colored accordingly (red for proteins quantified only in COVID-19 patients, orange for proteins with higher abundance in COVID-19 patients, and light blue for proteins with higher abundance in controls).
Figure 2
Figure 2
Western blot analysis for iron-related proteins in PBMCs isolated from COVID-19, long-COVID patients, and healthy controls. (A) Panels report the proteins levels for CP, Tf, HPX, LCN2, SOD1 and ACTIN in PBMCs isolated from COVID-19 patients (n = 7), long-COVID (n = 7) patients, and healthy volunteer donors (n = 7). (B) Band intensities were quantified using Image J and are reported in the figure as arbitrary units (AU). Data reported in this figure are the mean ± SE of two independent experiments (* p < 0.1, ** p < 0.01, *** p < 0.001).
Figure 3
Figure 3
5-LOX is modulated in COVID-19 and long-COVID patients. (A) 5-LOX protein levels were analyzed in PBMCs isolated from COVID-19 patients (n = 7), long-COVID (n = 7), and healthy donors (n = 7) using Western blot, and (B) bands intensities were quantified using Image J and reported as arbitrary units (AU). Data reported in this figure are the mean ± SE of two independent experiments (* p < 0.1, *** p < 0.001).
Figure 4
Figure 4
Increased LTB4 and LCN2 systemic levels in COVID-19 and long-COVID patients. (A,B) Plasma levels of LTB4 and LCN2 in COVID-19 patients (n = 30), long-COVID-19 patients (n = 10), and healthy donors (n = 25) were analyzed using ELISA. Data reported in this figure are the mean ± SE of two independent experiments (** p < 0.01).
Figure 5
Figure 5
Schematic representation of pathogenesis of SARS-CoV-2 infection and possible defense mechanisms.
See this image and copyright information in PMC

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