SARS-CoV-2 infects red blood cell progenitors and dysregulates hemoglobin and iron metabolism

ABSTRACT

Background: COVID-19, an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes acute respiratory symptoms and is reported to affect the vascular system, which may be underlying the systemic symptoms observed in affected patients. However, severe cases were reported to be associated with reduced erythrocyte (RBCs) turnover, low hemoglobin (Hb) 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 Hb homeostasis and aggravates COVID19 disease. Method(s) RBC precursors derived from peripheral CD34+ blood stem cells of healthy donors were infected in vitro with SARS-CoV-2 alpha variant and differentiated into RBCs. Hb and iron metabolism in more than 20 hospitalized Covid-19 patients and controls were analyzed in plasma-reduced whole blood samples using different approaches. Result(s) RBC precursors express ACE2 receptor, CD26 and CD147 at day 5 of differentiation, which makes them susceptible to SARS-CoV-2 infection, but virus is not able o replicate in these cell. qPCR analysis of differentiated RBCs revealed increased HAMP mRNA expression levels, encoding for hepcidin, which inhibits iron uptake. Furthermore, we found significantly changes in spin state of the iron in Hb as well as the tertiary structure shown by the formation of disulfide bridges in samples of COVID-19 patients. In addition, COVID-19 patients showed impaired Hb biosynthesis, enhanced formation of zinc-protoporphyrine IX, heme-CO2, and CO-Hb as well as degradation of Fe-heme. Moreover, significant iron dysmetablolism with high serum ferritin and low iron and transferrin levels occurred, explaining disturbances of oxygen-binding capacity observed in severely ill COVID-19 patients. Conclusion(s) Our data identify RBC precursors as a direct target of SARSCoV- 2 and suggest that SARS-CoV-2 induced dysregulation in Hb- and iron-metabolism contributes to the severe systemic course of COVID-19. Because changes in Hb structure may also be significantly involved in the development of Long-COVID symptoms such as fatigue and exhaustion, our findings may open the door for new diagnostic and therapeutic strategies for both intensive care COVID-19 patients and Long-COVID patients.