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1.
Stem Cell Rev Rep ; 18(5): 1809-1821, 2022 06.
Article in English | MEDLINE | ID: covidwho-1704701

ABSTRACT

BACKGROUND: SARS-CoV-2 infection causes acute respiratory distress, which may progress to multiorgan failure and death. Severe COVID-19 disease is accompanied by reduced erythrocyte turnover, low hemoglobin levels along with increased total bilirubin and ferritin serum concentrations. Moreover, expansion of erythroid progenitors in peripheral blood together with hypoxia, anemia, and coagulopathies highly correlates with severity and mortality. We demonstrate that SARS-CoV-2 directly infects erythroid precursor cells, impairs hemoglobin homeostasis and aggravates COVID-19 disease. METHODS: Erythroid precursor cells derived from peripheral CD34+ blood stem cells of healthy donors were infected in vitro with SARS-CoV-2 alpha variant and differentiated into red blood cells (RBCs). Hemoglobin and iron metabolism in hospitalized COVID-19 patients and controls were analyzed in plasma-depleted whole blood samples. Raman trapping spectroscopy rapidly identified diseased cells. RESULTS: RBC precursors express ACE2 receptor and CD147 at day 5 of differentiation, which makes them susceptible to SARS-CoV-2 infection. qPCR analysis of differentiated RBCs revealed increased HAMP mRNA expression levels, encoding for hepcidin, which inhibits iron uptake. COVID-19 patients showed impaired hemoglobin biosynthesis, enhanced formation of zinc-protoporphyrine IX, heme-CO2, and CO-hemoglobin as well as degradation of Fe-heme. Moreover, significant iron dysmetablolism with high serum ferritin and low serum iron and transferrin levels occurred, explaining disturbances of oxygen-binding capacity in severely ill COVID-19 patients. CONCLUSIONS: Our data identify RBC precursors as a direct target of SARS-CoV-2 and suggest that SARS-CoV-2 induced dysregulation in hemoglobin- and iron-metabolism contributes to the severe systemic course of COVID-19. This opens the door for new diagnostic and therapeutic strategies.


Subject(s)
COVID-19 , SARS-CoV-2 , Erythrocytes/metabolism , Ferritins , Heme/metabolism , Hemoglobins/metabolism , Humans , Iron/metabolism
2.
Sci Adv ; 7(22)2021 05.
Article in English | MEDLINE | ID: covidwho-1388434

ABSTRACT

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo-electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.


Subject(s)
COVID-19/immunology , Heme/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/immunology , Bilirubin/metabolism , Biliverdine/metabolism , Cryoelectron Microscopy , Crystallography, X-Ray , Epitopes , Humans , Immune Sera , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity
3.
Free Radic Res ; 55(7): 745-756, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1258678

ABSTRACT

It has been shown that the development of coronavirus infection (COVID-19), especially in severe cases, is accompanied by hypoxia as a result of several pathological processes: alveolar blood supply disorders, hemolysis, COVID-associated coagulopathy. Under these conditions, the level of reactive oxygen species is increased and it is more likely that free-radical damage to biomolecules is caused by the process of free-radical fragmentation than oxidation. In contrast to the oxidation process, free-radical fragmentation reactions are more effectively inhibited by oxidizing agents than reducing agents. Therefore, the use of substances possessing both reducing and oxidizing properties, such as natural and synthetic quinones, bioflavonoids, curcuminoids, should reduce the probability of biomolecule destruction by oxidation as well as free-radical fragmentation processes.HighlightsCOVID-19 is accompanied by the iron release from the heme and «silent¼ hypoxiaROS initiate fragmentation reactions of biomolecules under conditions of hypoxiaBlocking of fragmentation process by oxidizers may lead to mitigation of COVID-19.


Subject(s)
COVID-19/metabolism , Free Radicals/metabolism , SARS-CoV-2/metabolism , COVID-19/pathology , COVID-19/virology , Free Radicals/adverse effects , Heme/metabolism , Humans , Iron/metabolism , Oxidation-Reduction/drug effects , Reactive Oxygen Species/adverse effects , Reactive Oxygen Species/metabolism , SARS-CoV-2/pathogenicity
4.
Biomolecules ; 11(5)2021 04 27.
Article in English | MEDLINE | ID: covidwho-1215327

ABSTRACT

The SARS-CoV-2 outbreak was declared a worldwide pandemic in 2020. Infection triggers the respiratory tract disease COVID-19, which is accompanied by serious changes in clinical biomarkers such as hemoglobin and interleukins. The same parameters are altered during hemolysis, which is characterized by an increase in labile heme. We present two computational-experimental approaches aimed at analyzing a potential link between heme-related and COVID-19 pathophysiologies. Herein, we performed a detailed analysis of the common pathways induced by heme and SARS-CoV-2 by superimposition of knowledge graphs covering heme biology and COVID-19 pathophysiology. Focus was laid on inflammatory pathways and distinct biomarkers as the linking elements. In a second approach, four COVID-19-related proteins, the host cell proteins ACE2 and TMPRSS2 as well as the viral proteins 7a and S protein were computationally analyzed as potential heme-binding proteins with an experimental validation. The results contribute to the understanding of the progression of COVID-19 infections in patients with different clinical backgrounds and may allow for a more individual diagnosis and therapy in the future.


Subject(s)
COVID-19/metabolism , Heme/metabolism , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Computational Biology , Hemolysis , Host-Pathogen Interactions , Humans , Inflammation/metabolism , Inflammation/pathology , Models, Biological , Models, Molecular , Protein Binding , Protein Interaction Maps , Serine Endopeptidases/metabolism , Viral Proteins/metabolism
5.
Free Radic Biol Med ; 161: 263-271, 2020 12.
Article in English | MEDLINE | ID: covidwho-872071

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to infect hundred thousands of people every day worldwide. Since it is a novel virus, research continues to update the possible therapeutic targets when new evidence regarding COVID-19 are gathered. This article presents an evidence-based hypothesis that activating the heme oxygenase-1 (HO-1) pathway is a potential target for COVID-19. Interferons (IFNs) have broad-spectrum antiviral activity including against SARS-CoV-2. Induction of HO-1 and increase in the heme catabolism end-product confer antiviral activity. IFN activation results in inhibition of viral replication in various viral infections. COVID-19 induced inflammation as well as acute respiratory distress syndrome (ARDS), and coagulopathies are now known major causes of mortality. A protective role of HO-1 induction in inflammation, inflammation-induced coagulation, and ARDS has been reported. Based on an association of HO-1 promoter polymorphisms and disease severity, we propose an evaluation of the status of these polymorphisms in COVID-19 patients who become severely ill. If an association is established, it might be helpful in identifying patients at high risk. Hence, we hypothesize that HO-1 pathway activation could be a therapeutic strategy against COVID-19 and associated complications.


Subject(s)
COVID-19/immunology , Fibrinolytic Agents/metabolism , Heme Oxygenase-1/metabolism , Interferon Type I/immunology , SARS-CoV-2/growth & development , Antiviral Agents/metabolism , COVID-19/drug therapy , Disseminated Intravascular Coagulation/prevention & control , Heme/metabolism , Heme Oxygenase-1/genetics , Humans , Polymorphism, Single Nucleotide/genetics , SARS-CoV-2/drug effects
6.
J Microbiol Immunol Infect ; 54(1): 113-116, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-866905

ABSTRACT

Increased heme levels, anemia, and desaturation occur during infection. We aimed to compare the levels of heme, heme oxygenase-1 (HO-1), ferritin, and bilirubin in coronavirus disease 2019 (COVID-19) patients at different saturation levels. Heme and HO-1 enzyme levels significantly increased in the low SpO2 group, but further studies are required.


Subject(s)
COVID-19/metabolism , Heme Oxygenase-1/blood , Heme/metabolism , Adult , Bilirubin/blood , COVID-19/blood , COVID-19/enzymology , Female , Ferritins/blood , Humans , Male , Middle Aged , Oximetry , Prognosis , SARS-CoV-2/isolation & purification
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