Cross-talk between red blood cells and plasma influences blood flow and omics phenotypes in severe COVID-19
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This report illustrates the marked alteration of red blood cell (RBC) morphology that occurs with COVID-19 infection. Of particular importance is the observation that RBC morphology is dramatically affected whether cells are suspended in plasma from healthy vs COVID-infected blood. 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.
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Abstract
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.
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eLife assessment
This report illustrates the marked alteration of red blood cell (RBC) morphology that occurs with COVID-19 infection. Of particular importance is the observation that RBC morphology is dramatically affected whether cells are suspended in plasma from healthy vs COVID-infected blood. 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.
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Reviewer #1 (Public Review):
This paper describes detailed experiments to characterize the morphology and deformability, of red blood cells (RBCs) from COVID patients as compared to healthy individuals. Deformability is characterized by the visualization of cell shapes during flow in a microfluidic channel at high strain rates. One important feature of the study is that it considers the changes in patient RBCs when placed in healthy plasma and vice versa. An important observation is that the changes to RBCs properties appear, from this report, to be reversible - diseased cells revert to normal morphology and deformability upon immersion in healthy plasma. It also reports metabolics and proteomics analyses to shed light on the connections between the biochemical environment and RBC properties. One important question with regard to the …
Reviewer #1 (Public Review):
This paper describes detailed experiments to characterize the morphology and deformability, of red blood cells (RBCs) from COVID patients as compared to healthy individuals. Deformability is characterized by the visualization of cell shapes during flow in a microfluidic channel at high strain rates. One important feature of the study is that it considers the changes in patient RBCs when placed in healthy plasma and vice versa. An important observation is that the changes to RBCs properties appear, from this report, to be reversible - diseased cells revert to normal morphology and deformability upon immersion in healthy plasma. It also reports metabolics and proteomics analyses to shed light on the connections between the biochemical environment and RBC properties. One important question with regard to the changes in COVID-RBC properties with respect to plasma composition is whether the effect is simply due to dilution - are the factors responsible for the pathological morphology just diluted away when the cells are immersed in plasma that does not contain them? The studies are performed at very low hematocrit, so the composition equilibrium established here will not correspond to physiological conditions. This issue needs further discussion.
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Reviewer #2 (Public Review):
The authors addressed a timely and challenging topic, namely the role played by red blood cells (RBCs) and blood plasma in Covid-19 disease.
A remarkable feature reported here is that RBC from patients exhibits a notable morphological change, whereas when suspended in plasma control (healthy) exhibit normal shapes. Conversely, RBCs from healthy donors suspended in patients' plasma undergo similar morphological alteration as do RBCs of patients suspended in their plasma. Another important fact reported here is that RBCs affect plasma composition in a nontrivial way.
The data reported here cover a large panel of features, ranging from RBC morphological changes, plasma metabolites, and protein alteration, to collective RBC formation, in the form of clusters. They should constitute a precious enrichment of …
Reviewer #2 (Public Review):
The authors addressed a timely and challenging topic, namely the role played by red blood cells (RBCs) and blood plasma in Covid-19 disease.
A remarkable feature reported here is that RBC from patients exhibits a notable morphological change, whereas when suspended in plasma control (healthy) exhibit normal shapes. Conversely, RBCs from healthy donors suspended in patients' plasma undergo similar morphological alteration as do RBCs of patients suspended in their plasma. Another important fact reported here is that RBCs affect plasma composition in a nontrivial way.
The data reported here cover a large panel of features, ranging from RBC morphological changes, plasma metabolites, and protein alteration, to collective RBC formation, in the form of clusters. They should constitute a precious enrichment of relevant information regarding the intricate response of organisms to the Covid-19 virus.
This work will be of the potential impact on the community aiming to decipher the multifactorial impacts of blood components on patients suffering Covid-19.
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SciScore for 10.1101/2022.03.31.22273226: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: 2.1 Blood collection: Nine mL of blood is drawn in heparin tubes from five healthy volunteers under informed consent and 14 COVID-19 patients admitted at the Intensive Care Unit (ICU) at the Frankfurt University Hospital, seven of which with supported ventilation and six receiving extracorporeal membrane oxygenation (ECMO) (Online Supplementary Table S1).
IRB: The study is performed according to the Declaration of Helsinki and under the approval of the Fraunhofer Institute for Translational Medicine and Pharmacology ethics committee (reference #20-643, #20-982).Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table …
SciScore for 10.1101/2022.03.31.22273226: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: 2.1 Blood collection: Nine mL of blood is drawn in heparin tubes from five healthy volunteers under informed consent and 14 COVID-19 patients admitted at the Intensive Care Unit (ICU) at the Frankfurt University Hospital, seven of which with supported ventilation and six receiving extracorporeal membrane oxygenation (ECMO) (Online Supplementary Table S1).
IRB: The study is performed according to the Declaration of Helsinki and under the approval of the Fraunhofer Institute for Translational Medicine and Pharmacology ethics committee (reference #20-643, #20-982).Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources 2.4 Flow analysis: Velocity, lateral cell position in the y-direction, and projection area of each cell are determined using a customized python script. pythonsuggested: (IPython, RRID:SCR_001658)Additional analyses, including untargeted analyses and Fish score calculation via MS/MS, are calculated against the ChemSpider database with Compound Discoverer 2.0 (Thermo Fisher, Bremen, Germany). 2.7 Proteomics: Proteomics analyses are performed via filter aided sample preparation (FASP) digestion and nano UHPLC-MS/MS identification (TIMS TOF Pro 2 Single Cell Proteomics, Bruker Daltonics, Bremen, Germany), as previously described (24). ChemSpidersuggested: (ChemSpider, RRID:SCR_006360)2.8 Statistical analyses: Graphical representations and statistical analyses by T-test, repeated measures ANOVA or Kruskal-Wallis test are performed with GraphPad Prism (GraphPad Software, Inc, La Jolla, CA) GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798), MATLAB (MathWorks, Natick, MA), and MetaboAnalyst 5.0. MATLABsuggested: (MATLAB, RRID:SCR_001622)MetaboAnalystsuggested: (MetaboAnalyst, RRID:SCR_015539)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- No funding statement was detected.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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