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

Romy Kronstein-Wiedemann,Torsten Tonn,Sofia Traikov,Karin Schütze,Michael Wagner,Mandy Georgi,Hesham Yosef,Marlena Stadtmüller,Jan Wallenborn,Ali El-Armouche,Madeleine Teichert,Andreas Karl

doi:10.1007/s12015-021-10322-8

Abstract

BackgroundSARS-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.MethodsErythroid 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.ResultsRBC 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.ConclusionsOur 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

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is the cause of the worldwide COVID-19 pandemic
There was a strong upregulation of the mRNA levels of hepcidin antimicrobial peptide (HAMP), which codes for hepcidin, the main regulator of iron homeostasis [10], after SARS-CoV-2 infection in the CECs of all donors (Fig. 1d)
◂Fig. 4 COVID-19 patients show enhanced expression of enzymes involved in iron and hemoglobin metabolism. a Relative expression of HAMP mRNA to the mean ΔCT value healthy donors

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is the cause of the worldwide COVID-19 pandemic. Severe cases are associated with reduced erythrocyte turnover and low hemoglobin levels along with increased total bilirubin and ferritin concentrations. Severe COVID-19 disease is accompanied by reduced erythrocyte turnover, low hemoglobin levels along with increased total bilirubin and ferritin serum concentrations. We demonstrate that SARS-CoV-2 directly infects erythroid precursor cells, impairs hemoglobin homeostasis and aggravates COVID-19 disease. 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

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Conclusion