SARS-CoV-2 Infects Red Blood Cell Progenitors and Dysregulates Hemoglobin and Iron Metabolism

Stem Cell Reviews and Reports - Tập 18 Số 5 - Trang 1809-1821 - 2022
Romy Kronstein‐Wiedemann1, Marlena Stadtmüller2, Sofia Traikov3, Mandy Georgi4, Madeleine Teichert1, Hesham K. Yosef5, Jan Wallenborn4, Andreas Karl6, Karin Schütze5, Michael Wagner7, Ali El‐Armouche8, Torsten Tonn9
1Department of Transfusion Medicine, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße. 74, 01307, Dresden, Germany
2Institute of Medical Microbiology and Virology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße. 74, 01307, Dresden, Germany
3Max-Planck-Institute of Molecular Cell Biology and Genetic, Pfotenhauerstr. 108, 01307, Dresden, Germany
4Clinic of Anaesthesiology and Intensive Care Medicine, HELIOS Clinic, Gartenstraße 6, 08280, Aue, Germany
5CellTool GmbH, Lindemannstraße 13, 82327, Tutzing, Germany
6German Red Cross Blood Donation Service North-East, Institute for Transfusion Medicine, Röntgenstraße 2a, 08529, Plauen, Germany
7Clinic for Internal Medicine and Cardiology, Heart Center Dresden, Technische Universität Dresden, Fetscherstraße. 76, 01307, Dresden, Germany
8Institute of Clinical Pharmacology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße. 74, 01307, Dresden, Germany
9German Red Cross Blood Donation Service North-East, Institute for Transfusion Medicine, Blasewitzer Straße. 68/70, 01307, Dresden, Germany

Tóm tắt

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. Graphical Abstract

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Tài liệu tham khảo

Terpos, E., Ntanasis-Stathopoulos, I., Elalamy, I., et al. (2020). Hematological findings and complications of COVID-19. American Journal of Hematology, 95(7), 834–847.

San Juan, I., Bruzzone, C., Bizkarguenaga, M., et al. (2020). Abnormal concentration of porphyrins in serum from COVID-19 patients. British Journal of Haematology.

Xu, Z., Shi, L., Wang, Y., et al. (2020). Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet Respiratory Medicine, 8(4), 420–422.

Mohanty, J. G., Nagababu, E., & Rifkind, J. M. (2014). Red blood cell oxidative stress impairs oxygen delivery and induces red blood cell aging. Frontiers in Physiology, 5, 84.

Thomas, T., Stefanoni, D., Dzieciatkowska, M., et al. (2020). Evidence for structural protein damage and membrane lipid remodeling in red blood cells from COVID-19 patients. medRxiv.

Muckenthaler, M. U., Rivella, S., Hentze, M. W., et al. (2017). A red carpet for Iron metabolism [in eng]. Cell, 168(3), 344–361.

Cavezzi, A., Troiani, E., & Corrao, S. (2020). COVID-19: Hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clinical Practice, 10(2), 1271.

Liu W, Li H. (2020). COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Heme Metabolism. Prelimnary Report.

Wenzhong, T., Hualan, L. (2020). Attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. ChemRxiv, Preprint. https://doi.org/10.26434/chemrxiv.11938173.v8.

Taneri, P. E., Gomez-Ochoa, S. A., Llanaj, E., et al. (2020). Anemia and iron metabolism in COVID-19: A systematic review and meta-analysis. European Journal of Epidemiology, 35(8), 763–773.

Hoffmann, M., Kleine-Weber, H., Schroeder, S., et al. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181(2), 271–280 e278.

Li, Y., Zhang, Z., Yang, L., et al. (2020). The MERS-CoV Receptor DPP4 as a Candidate Binding Target of the SARS-CoV-2 Spike. iScience, 23(6), 101160.

Wang, K., Chen, W., Zhang, Z., et al. (2020). CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells. Signal Transduction and Targeted Therapy, 5(1), 283.

Pellegrini, L., Albecka, A., Mallery, D. L., et al. (2020). SARS-CoV-2 infects the brain choroid plexus and disrupts the blood-CSF barrier in human brain organoids. Cell Stem Cell, 27(6), 951–961 e955.

Sungnak, W., Huang, N., Becavin, C., et al. (2020). SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nature Medicine, 26(5), 681–687.

Wang, Y., Liu, S., Liu, H., et al. (2020). SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. Journal of Hepatology, 73(4), 807–816.

Ratajczak, M. Z., Bujko, K., Ciechanowicz, A., et al. (2021). SARS-CoV-2 entry receptor ACE2 is expressed on very small CD45(−) precursors of hematopoietic and endothelial cells and in response to virus spike protein activates the Nlrp3 Inflammasome. Stem Cell Reviews and Reports, 17(1), 266–277.

Bernardes, J. P., Mishra, N., Tran, F., et al. (2020). Longitudinal multi-omics analyses identify responses of megakaryocytes, erythroid cells, and Plasmablasts as hallmarks of severe COVID-19. Immunity, 53(6), 1296–1314 e1299.

Grzywa, T. M., Nowis, D., & Golab, J. (2021). The role of CD71(+) erythroid cells in the regulation of the immune response. Pharmacology & Therapeutics, 228, 107927.

Huerga Encabo, H., Grey, W., Garcia-Albornoz, M., et al. (2021). Human erythroid progenitors are directly infected by SARS-CoV-2: Implications for emerging erythropoiesis in severe COVID-19 patients. Stem Cell Reports, 16(3), 428–436.

Shahbaz, S., Xu, L., Osman, M., et al. (2021). Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2. Stem Cell Reports, 16(5), 1165–1181.

Giarratana, M. C., Rouard, H., Dumont, A., et al. (2011). Proof of principle for transfusion of in vitro-generated red blood cells [clinical trial in vitro] [in eng]. Blood, 118(19), 5071–5079.

Schuhmann, K., Thomas, H., Ackerman, J. M., et al. (2017). Intensity-independent noise filtering in FT MS and FT MS/MS spectra for shotgun Lipidomics. Analytical Chemistry, 89(13), 7046–7052.

Schuhmann, K., Srzentic, K., Nagornov, K. O., et al. (2017). Monitoring membrane Lipidome turnover by metabolic (15)N labeling and shotgun ultra-high-resolution Orbitrap Fourier transform mass spectrometry. Analytical Chemistry, 89(23), 12857–12865.

Herzog, R., Schuhmann, K., Schwudke, D., et al. (2012). LipidXplorer: A software for consensual cross-platform lipidomics. PLoS One, 7(1), e29851.

Dowdle, W. E., Nyfeler, B., Nagel, J., et al. (2014). Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nature Cell Biology, 16(11), 1069–1079.

Das, T. K., Couture, M., Ouellet, Y., et al. (2001). Simultaneous observation of the O---O and Fe---O2 stretching modes in oxyhemoglobins. Proceedings of the National Academy of Sciences of the United States of America, 98(2), 479–484.

Jacob, S. S., Bankapur, A., Barkur, S., et al. (2020). Micro-Raman spectroscopy analysis of optically trapped erythrocytes in jaundice. Frontiers in Physiology, 11, 821.

Wen, Z. Q. (2007). Raman spectroscopy of protein pharmaceuticals. Journal of Pharmaceutical Sciences, 96(11), 2861–2878.

Wood, B. R., Caspers, P., Puppels, G. J., et al. (2007). Resonance Raman spectroscopy of red blood cells using near-infrared laser excitation. Analytical and Bioanalytical Chemistry, 387(5), 1691–1703.

Labbe, R. F., Vreman, H. J., & Stevenson, D. K. (1999). Zinc protoporphyrin: A metabolite with a mission. Clinical Chemistry, 45(12), 2060–2072.

Ajioka, R. S., Phillips, J. D., & Kushner, J. P. (2006). Biosynthesis of heme in mammals. Biochimica et Biophysica Acta, 1763(7), 723–736.

Anka, A. U., Tahir, M. I., Abubakar, S. D., et al. (2021). Coronavirus disease 2019 (COVID-19): An overview of the immunopathology, serological diagnosis and management. Scandinavian Journal of Immunology, 93(4), e12998.

Ropa, J., Cooper, S., Capitano, M. L., et al. (2021). Human hematopoietic stem, progenitor, and immune cells respond ex vivo to SARS-CoV-2 spike protein. Stem Cell Reviews and Reports, 17(1), 253–265.

Kucia, M., Ratajczak, J., Bujko, K., et al. (2021). An evidence that SARS-Cov-2/COVID-19 spike protein (SP) damages hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3 inflammasome-dependent manner. Leukemia, 35(10), 3026–3029.

Ginzburg, Y. Z. (2019). Hepcidin-ferroportin axis in health and disease. Vitamins and Hormones, 110, 17–45.

Mancias, J. D., Pontano Vaites, L., Nissim, S., et al. (2015). Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. Elife, 4.

Ryu, M. S., Zhang, D., Protchenko, O., et al. (2017). PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis. The Journal of Clinical Investigation, 127(5), 1786–1797.

Gao, X., Lee, H. Y., Li, W., et al. (2017). Thyroid hormone receptor beta and NCOA4 regulate terminal erythrocyte differentiation. Proceedings of the National Academy of Sciences of the United States of America, 114(38), 10107–10112.

Rein, H., & Ristau, O. (1965). Evidence of high-spin and low-spin form of hemoproteins using electron spin resonance. Biochimica et Biophysica Acta, 94, 516–524.

Ryter, S. W. (2021). Significance of Heme and Heme degradation in the pathogenesis of acute lung and inflammatory disorders. International Journal of Molecular Sciences, 22(11).

Phillips, J. D. (2019). Heme biosynthesis and the porphyrias. Molecular Genetics and Metabolism, 128(3), 164–177.

Braun, J. (1999). Erythrocyte zinc protoporphyrin. Kidney International. Supplement, 69, S57–S60.

Cole, S. P., & Marks, G. S. (1984). Ferrochelatase and N-alkylated porphyrins. Molecular and Cellular Biochemistry, 64(2), 127–137.

Okado-Matsumoto, A., & Fridovich, I. (2001). Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu, Zn-SOD in mitochondria. Journal of Biological Chemistry, 276(42), 38388–38393.

Katsarou, A., & Pantopoulos, K. (2018). Hepcidin therapeutics. Pharmaceuticals, 11(127), 1–30.

Group RC, Horby, P., Lim, W. S., et al. (2021). Dexamethasone in hospitalized patients with Covid-19. The New England Journal of Medicine, 384(8), 693–704.

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Stem Cell Reviews and Reports

Tập 18 Số 5

1809-1821

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