Evidence for structural protein damage and membrane lipid remodeling in red blood cells from COVID-19 patients

Abstract

The SARS-CoV-2 beta coronavirus is the etiological driver of COVID-19 disease, which is primarily characterized by shortness of breath, persistent dry cough, and fever. Because they transport oxygen, red blood cells (RBCs) may play a role in the severity of hypoxemia in COVID-19 patients. The present study combines state-of-the-art metabolomics, proteomics, and lipidomics approaches to investigate the impact of COVID-19 on RBCs from 23 healthy subjects and 29 molecularly-diagnosed COVID-19 patients. RBCs from COVID-19 patients had increased levels of glycolytic intermediates, accompanied by oxidation and fragmentation of ankyrin, spectrin beta, and the N-terminal cytosolic domain of band 3 (AE1). Significantly altered lipid metabolism was also observed, especially short and medium chain saturated fatty acids, acyl-carnitines, and sphingolipids. Nonetheless, there were no alterations of clinical hematological parameters, such as RBC count, hematocrit, and mean corpuscular hemoglobin concentration, with only minor increases in mean corpuscular volume. Taken together, these results suggest a significant impact of SARS-CoV-2 infection on RBC structural membrane homeostasis at the protein and lipid levels. Increases in RBC glycolytic metabolites are consistent with a theoretically improved capacity of hemoglobin to off-load oxygen as a function of allosteric modulation by high-energy phosphate compounds, perhaps to counteract COVID-19-induced hypoxia. Conversely, because the N-terminus of AE1 stabilizes deoxyhemoglobin and finely tunes oxygen off-loading, RBCs from COVID-19 patients may be incapable of responding to environmental variations in hemoglobin oxygen saturation when traveling from the lungs to peripheral capillaries and, as such, may have a compromised capacity to transport and deliver oxygen.

Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2

“…in malaria), resulting in hemolysis 16 . In support of this concept, structural protein damage and changes in RBC membrane lipids have been reported in COVID-19 patients 17 . In addition to ACE2, SARS-CoV-2 invades host cells via CD147 18 , a known RBC receptor for Plasmodium falciparum 19 .…”

“…We also observed increased number of light weight RBCs (CD235a+CD71-) in the circulation of these patients. This suggests that SARS-CoV-2 infection or the immunopathology associated with COVID-19 disease can modify RBCs and/or CEC structural components, and was illustrated by a recent report that COVID-19 infection is associated with RBC structural protein damage and modifications in RBC membrane lipids 17 . Although this study was conducted on mature RBCs, it is possible that COVID-19 infection can also alter CEC deformability.…”

“…Elevated cytokines (e.g. IL-1, IL-6 and TNF-a) may influence erythropoiesis 55 and increase the permissibility of RBCs to oxidant stress-induced lysis in COVID-19 patients 17 . In light of the above, there is the possibility that SARS-CoV-2 infection directly or indirectly invades RBCs in the periphery or the bone marrow resulting in their enhanced lysis and anemia 45,46,56 .…”

Red blood cell exchange for SARS-CoV-2: A Gemini of therapeutic opportunities

“…Some experience symptoms most reminiscent of hypoxia and now, red blood cells (RBCs) have been found altered in patients infected with SARS-CoV-2. One of the most significant studies utilized state-of-the-art topologies to investigate the metabolomic, proteomic, and lipidomic effects of COVID-19 on RBCs [13] .…”

How could we forget immunometabolism in SARS-CoV2 infection or COVID-19?

“…Hence, a decrease in the circulating S1P in the COVID-19 patients indicates the decreased number of T cells in the circulation, but an increase in the inflamed organ, which is more in severe COVID-19 patients. The SARS-CoV2 infection to the RBCs, platelets (thrombocytopenia), and vascular endothelial cells decreases the circulating S1P in the COVID-19 patients [118][119][120][121][122]. The SARS-CoV2 infection of RBCs alters their oxygen-carrying capacity, lipid metabolism (especially short and medium-chain saturated fatty acids, acyl-carnitines, and sphingolipids), and glucose metabolism (glycolysis).…”