Geometry-matching
has been known to benefit the formation of stable
biological interactions in natural systems. Herein, we report that
the spiky nanostructures with matched topography to the influenza
A virus (IAV) virions could be used to design next-generation advanced
virus inhibitors. We demonstrated that nanostructures with spikes
between 5 and 10 nm bind significantly better to virions than smooth
nanoparticles, due to the short spikes inserting into the gaps of
glycoproteins of the IAV virion. Furthermore, an erythrocyte membrane
(EM) was coated to target the IAV, and the obtained EM-coated nanostructures
could efficiently prevent IAV virion binding to the cells and inhibit
subsequent infection. In a postinfection study, the EM-coated nanostructures
reduced >99.9% virus replication at the cellular nontoxic dosage.
We predict that such a combination of geometry-matching topography
and cellular membrane coating will also push forward the development
of nanoinhibitors for other virus strains, including SARS-CoV-2.
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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