Cross-talk between red blood cells and plasma influences blood flow and omics phenotypes in severe COVID-19

Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and can affect multiple organs, among which is the circulatory system. Inflammation and mortality risk markers were previously detected in COVID-19 plasma and red blood cells (RBCs) metabolic and proteomic profiles. Additionally, biophysical properties, such as deformability, were found to be changed during the infection. Based on such data, we aim to better characterize RBC functions in COVID-19. We evaluate the flow properties of RBCs in severe COVID-19 patients admitted to the intensive care unit by using microfluidic techniques and automated methods, including artificial neural networks, for an unbiased RBC analysis. We find strong flow and RBC shape impairment in COVID-19 samples and demonstrate that such changes are reversible upon suspension of COVID-19 RBCs in healthy plasma. Vice versa, healthy RBCs resemble COVID-19 RBCs when suspended in COVID-19 plasma. Proteomics and metabolomics analyses allow us to detect the effect of plasma exchanges on both plasma and RBCs and demonstrate a new role of RBCs in maintaining plasma equilibria at the expense of their flow properties. Our findings provide a framework for further investigations of clinical relevance for therapies against COVID-19 and possibly other infectious diseases. Editor's evaluation This report illustrates a comprehensive account detailing the marked alteration of red blood cell (RBC) morphology that occurs with COVID-19 infection. A particularly important result is the observation that RBC morphology is dramatically affected by plasma from COVID-19 patients and reversible with plasma from healthy donors. The claims of the manuscript are well supported by the data, and the approaches used are thoughtful and rigorous. The results are important for consideration of the broader pathophysiology of COVID-19, particularly with regard to the impact on vascular biology and will be of interest to the readership of eLife