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

[en] 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.

Disciplines :

Physics

Author, co-author :

Recktenwald, Steffen M.

Simionato, Greta

Lopes, Marcelle G. M.

Gamboni, Fabia

Dzieciatkowska, Monika

Meybohm, Patrick

Zacharowski, Kai

von Knethen, Andreas

WAGNER, Christian ; University of Luxembourg

Kaestner, Lars

More authors (6 more)

External co-authors :

yes

Language :

English

Title :

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

Publication date :

2022

Journal title :

eLife

eISSN :

2050-084X

Publisher :

eLife Sciences Publications, Ltd

Volume :

Pages :

e81316

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://doi.org/10.7554/eLife.81316

Available on ORBilu :

since 03 July 2023

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Bateman RM, Sharpe MD, Singer M, Ellis CG. 2017. The effect of sepsis on the erythrocyte. International Journal of Molecular Sciences 18:1932. DOI: https://doi.org/10.3390/ijms18091932, PMID: 28885563
Bernhardt I, Ellory JC. 2013. Red Cell Membrane Transport in Health and Disease. Springer Science & Business Media. DOI: https://doi.org/10.1007/978-3-662-05181-8
Bessis MC, Weed RI, Leblond PF. 1973. Red Cell Shape. Berlin, Heidelberg: Springer. DOI: https://doi.org/10. 1007/978-3-642-88062-9
Böning D, Kuebler WM, Bloch W. 2021. The oxygen dissociation curve of blood in covid-19. American Journal of Physiology. Lung Cellular and Molecular Physiology 321:L349–L357. DOI: https://doi.org/10.1152/ajplung. 00079.2021, PMID: 33978488
Bownik A, Stępniewska Z. 2016. Ectoine as a promising protective agent in humans and animals. Arhiv Za Higijenu Rada i Toksikologiju 67:260–265. DOI: https://doi.org/10.1515/aiht-2016-67-2837, PMID: 28033102
Burke AM, Quest DO, Chien S, Cerri C. 1981. The effects of mannitol on blood viscosity. Journal of Neurosurgery 55:550–553. DOI: https://doi.org/10.3171/jns.1981.55.4.0550, PMID: 6792325
Burnum-Johnson KE, Kyle JE, Eisfeld AJ, Casey CP, Stratton KG, Gonzalez JF, Habyarimana F, Negretti NM, Sims AC, Chauhan S, Thackray LB, Halfmann PJ, Walters KB, Kim Y-M, Zink EM, Nicora CD, Weitz KK, Webb-Robertson B-JM, Nakayasu ES, Ahmer B, et al. 2017. MPLEx: a method for simultaneous pathogen inactivation and extraction of samples for multi-OMICS profiling. The Analyst 142:442–448. DOI: https://doi. org/10.1039/c6an02486f, PMID: 28091625
Buttarelli FR, Fanciulli A, Pellicano C, Pontieri FE. 2011. The dopaminergic system in peripheral blood lymphocytes: from physiology to pharmacology and potential applications to neuropsychiatric disorders. Current Neuropharmacology 9:278–288. DOI: https://doi.org/10.2174/157015911795596612, PMID: 22131937
Byrnes JR, Wolberg AS. 2017. Red blood cells in thrombosis. Blood 130:1795–1799. DOI: https://doi.org/10. 1182/blood-2017-03-745349, PMID: 28811305
Caruso C, Fay ME, Cheng X, Liu AY, Park SI, Sulchek TA, Graham MD, Lam WA. 2022. Pathologic mechanobiological interactions between red blood cells and endothelial cells directly induce vasculopathy in iron deficiency anemia. IScience 25:104606. DOI: https://doi.org/10.1016/j.isci.2022.104606, PMID: 35800766
Claise C, Saleh J, Rezek M, Vaulont S, Peyssonnaux C, Edeas M. 2022. Low transferrin levels predict heightened inflammation in patients with covid-19: new insights. International Journal of Infectious Diseases 116:74–79. DOI: https://doi.org/10.1016/j.ijid.2021.12.340, PMID: 34952211
Conneely OM. 2001. Antiinflammatory activities of lactoferrin. Journal of the American College of Nutrition 20:389S–395S. DOI: https://doi.org/10.1080/07315724.2001.10719173, PMID: 11603648
D’Alessandro A, Thomas T, Dzieciatkowska M, Hill RC, Francis RO, Hudson KE, Zimring JC, Hod EA, Spitalnik SL, Hansen KC. 2020. Serum proteomics in COVID-19 patients: altered coagulation and complement status as a function of IL-6 level. Journal of Proteome Research 19:4417–4427. DOI: https://doi.org/10.1021/acs. jproteome.0c00365, PMID: 32786691
D’Alessandro A, Akpan I, Thomas T, Reisz J, Cendali F, Gamboni F, Nemkov T, Thangaraju K, Katneni U, Tanaka K, Kahn S, Wei A, Valk J, Hudson K, Roh D, Moriconi C, Zimring J, Hod E, Spitalnik S, Buehler P, et al. 2021a. Biological and clinical factors contributing to the metabolic heterogeneity of hospitalized patients with and without covid-19. Research Square 10:rs.3.rs-480167. DOI: https://doi.org/10.21203/rs.3.rs-480167/v1, PMID: 34013258
D’Alessandro A, Fu X, Kanias T, Reisz JA, Culp-Hill R, Guo Y, Gladwin MT, Page G, Kleinman S, Lanteri M, Stone M, Busch MP, Zimring JC, Recipient Epidemiology and Donor Evaluation Study-III REDS III. 2021b. Donor sex, age and ethnicity impact stored red blood cell antioxidant metabolism through mechanisms in part explained by glucose 6-phosphate dehydrogenase levels and activity. Haematologica 106:1290–1302. DOI: https://doi.org/10.3324/haematol.2020.246603, PMID: 32241843
Dasanna AK, Darras A, John T, Gompper G, Kaestner L, Wagner C, Fedosov DA. 2022. Erythrocyte sedimentation: effect of aggregation energy on gel structure during collapse. Physical Review. E 105:024610. DOI: https://doi.org/10.1103/PhysRevE.105.024610, PMID: 35291110
Della Rocca DG, Magnocavallo M, Lavalle C, Romero J, Forleo GB, Tarantino N, Chimenti C, Alviz I, Gamero MT, Garcia MJ, Di Biase L, Natale A. 2021. Evidence of systemic endothelial injury and microthrombosis in hospitalized COVID-19 patients at different stages of the disease. Journal of Thrombosis and Thrombolysis 51:571–576. DOI: https://doi.org/10.1007/s11239-020-02330-1, PMID: 33156441
Di Carlo D. 2012. A mechanical biomarker of cell state in medicine. Journal of Laboratory Automation 17:32–42. DOI: https://doi.org/10.1177/2211068211431630, PMID: 22357606
Galbraith MD, Kinning KT, Sullivan KD, Araya P, Smith KP, Granrath RE, Shaw JR, Baxter R, Jordan KR, Russell S, Dzieciatkowska M, Reisz JA, Gamboni F, Cendali F, Ghosh T, Guo K, Wilson CC, Santiago ML, Monte AA, Bennett TD, et al. 2022. Specialized interferon action in covid-19. PNAS 119:e2116730119. DOI: https://doi. org/10.1073/pnas.2116730119, PMID: 35217532
Guckenberger A, Kihm A, John T, Wagner C, Gekle S. 2018. Numerical-experimental observation of shape bistability of red blood cells flowing in a microchannel. Soft Matter 14:2032–2043. DOI: https://doi.org/10. 1039/c7sm02272g, PMID: 29473072
Issaian A, Hay A, Dzieciatkowska M, Roberti D, Perrotta S, Darula Z, Redzic J, Busch MP, Page GP, Rogers SC, Doctor A, Hansen KC, Eisenmesser EZ, Zimring JC, D’Alessandro A. 2021. The interactome of the N-terminus of band 3 regulates red blood cell metabolism and storage quality. Haematologica 106:2971–2985. DOI: https://doi.org/10.3324/haematol.2020.278252, PMID: 33979990
Janiaud P, Axfors C, Schmitt AM, Gloy V, Ebrahimi F, Hepprich M, Smith ER, Haber NA, Khanna N, Moher D, Goodman SN, Ioannidis JPA, Hemkens LG. 2021. Association of convalescent plasma treatment with clinical outcomes in patients with covid-19: a systematic review and meta-analysis. JAMA 325:1185–1195. DOI: https://doi.org/10.1001/jama.2021.2747, PMID: 33635310
Kaur G, Ji X, Rahman I. 2021. SARS-cov2 infection alters tryptophan catabolism and phospholipid metabolism. Metabolites 11:659. DOI: https://doi.org/10.3390/metabo11100659, PMID: 34677374
Kihm A, Kaestner L, Wagner C, Quint S. 2018. Classification of red blood cell shapes in flow using outlier tolerant machine learning. PLOS Computational Biology 14:e1006278. DOI: https://doi.org/10.1371/journal.pcbi. 1006278, PMID: 29906283
Kubánková M, Hohberger B, Hoffmanns J, Fürst J, Herrmann M, Guck J, Kräter M. 2021. Physical phenotype of blood cells is altered in COVID-19. Biophysical Journal 120:2838–2847. DOI: https://doi.org/10.1016/j.bpj. 2021.05.025, PMID: 34087216
Lanotte L, Mauer J, Mendez S, Fedosov DA, Fromental JMM, Claveria V, Nicoud F, Gompper G, Abkarian M, Mauer J, Fedosov DA, Gompper G, Mendez S, Nicoud F, Fromental JMM. 2016. Red cells’ dynamic morphologies govern blood shear thinning under microcirculatory flow conditions. PNAS 113:13289–13294. DOI: https://doi.org/10.1073/pnas.1608074113, PMID: 27834220
Lim H. 2009. Red Blood Cell Shapes and Shape Transformations: Newtonian Mechanics of a Composite Membrane: Sections 2.5–2.8, Chapter 2. Wiley-VCH Verlag GmbH & Co. KGaA.
Lipowsky HH. 2005. Microvascular rheology and hemodynamics. Microcirculation 12:5–15. DOI: https://doi.org/ 10.1080/10739680590894966, PMID: 15804970
Mangge H, Herrmann M, Meinitzer A, Pailer S, Curcic P, Sloup Z, Holter M, Prüller F. 2021. Increased kynurenine indicates a fatal course of COVID-19. Antioxidants 10:12. DOI: https://doi.org/10.3390/antiox10121960, PMID: 34943063
Mann ER, Menon M, Knight SB, Konkel JE, Jagger C, Shaw TN, Krishnan S, Rattray M, Ustianowski A, Bakerly ND, Dark P, Lord G, Simpson A, Felton T, Ho LP, Feldmann M, Grainger JR, Hussell T, Respiratory TRC, CIRCO. 2020. Longitudinal Immune Profiling Reveals Distinct Features of COVID-19 Pathogenesis. medRxiv. DOI: https://doi.org/10.1101/2020.06.13.20127605
Matthews K, Myrand-Lapierre ME, Ang RR, Duffy SP, Scott MD, Ma H. 2015. Microfluidic deformability analysis of the red cell storage lesion. Journal of Biomechanics 48:4065–4072. DOI: https://doi.org/10.1016/j.jbiomech. 2015.10.002, PMID: 26477408
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, HLH Across Speciality Collaboration, UK. 2020. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395:1033–1034. DOI: https://doi.org/10.1016/S0140-6736(20)30628-0, PMID: 32192578
Messner CB, Demichev V, Wendisch D, Michalick L, White M, Freiwald A, Textoris-Taube K, Vernardis SI, Egger AS, Kreidl M, Ludwig D, Kilian C, Agostini F, Zelezniak A, Thibeault C, Pfeiffer M, Hippenstiel S, Hocke A, von Kalle C, Campbell A, et al. 2020. Ultra-high-throughput clinical proteomics reveals classifiers of covid-19 infection. Cell Systems 11:11–24. DOI: https://doi.org/10.1016/j.cels.2020.05.012, PMID: 32619549
Minhas PS, Liu L, Moon PK, Joshi AU, Dove C, Mhatre S, Contrepois K, Wang Q, Lee BA, Coronado M, Bernstein D, Snyder MP, Migaud M, Majeti R, Mochly-Rosen D, Rabinowitz JD, Andreasson KI. 2019. Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation. Nature Immunology 20:50–63. DOI: https://doi.org/10.1038/s41590-018-0255-3, PMID: 30478397
Nataf S. 2020. An alteration of the dopamine synthetic pathway is possibly involved in the pathophysiology of covid-19. Journal of Medical Virology 92:1743–1744. DOI: https://doi.org/10.1002/jmv.25826, PMID: 32246784
Nemkov T, Reisz JA, Xia Y, Zimring JC, D’Alessandro A. 2018. Red blood cells as an organ? how deep omics characterization of the most abundant cell in the human body highlights other systemic metabolic functions beyond oxygen transport. Expert Review of Proteomics 15:855–864. DOI: https://doi.org/10.1080/14789450. 2018.1531710, PMID: 30278801
Nemkov T, Reisz JA, Gehrke S, Hansen KC, D’Alessandro A. 2019. High-throughput metabolomics: isocratic and gradient mass spectrometry-based methods. Nemkov JA (Ed). High-Throughput Metabolomics. Springer. p. 13–26. DOI: https://doi.org/10.1007/978-1-4939-9236-2_2
Piety NZ, Stutz J, Yilmaz N, Xia H, Yoshida T, Shevkoplyas SS. 2021. Microfluidic capillary networks are more sensitive than ektacytometry to the decline of red blood cell deformability induced by storage. Scientific Reports 11:604. DOI: https://doi.org/10.1038/s41598-020-79710-3, PMID: 33436749
Ponder E. 1948. Hemolysis and Related Phenomena. Saunders.
Pries AR, Secomb TW. 2008. Blood flow in microvascular networks. Pries AR (Ed). Microcirculation. Elsevier. p. 3–36. DOI: https://doi.org/10.1016/B978-0-12-374530-9.00001-2
Ramírez-Zamora S, Méndez-Rodríguez ML, Olguín-Martínez M, Sánchez-Sevilla L, Quintana-Quintana M, García-García N, Hernández-Muñoz R. 2013. Increased erythrocytes by-products of arginine catabolism are associated with hyperglycemia and could be involved in the pathogenesis of type 2 diabetes mellitus. PLOS ONE 8:e66823. DOI: https://doi.org/10.1371/journal.pone.0066823, PMID: 23826148
Recktenwald SM, Graessel K, Maurer FM, John T, Gekle S, Wagner C. 2022a. Red blood cell shape transitions and dynamics in time-dependent capillary flows. Biophysical Journal 121:23–36. DOI: https://doi.org/10.1016/j. bpj.2021.12.009, PMID: 34896369
Recktenwald SM, Lopes MGM, Peter S, Hof S, Simionato G, Peikert K, Hermann A, Danek A, van Bentum K, Eichler H, Wagner C, Quint S, Kaestner L. 2022b. Erysense, a lab-on-a-chip-based point-of-care device to evaluate red blood cell flow properties with multiple clinical applications. Frontiers in Physiology 13:884690. DOI: https://doi.org/10.3389/fphys.2022.884690, PMID: 35574449
Reinhart WH, Piety NZ, Deuel JW, Makhro A, Schulzki T, Bogdanov N, Goede JS, Bogdanova A, Abidi R, Shevkoplyas SS. 2015. Washing stored red blood cells in an albumin solution improves their morphologic and hemorheologic properties. Transfusion 55:1872–1881. DOI: https://doi.org/10.1111/trf.13052, PMID: 25752902
Renoux C, Fort R, Nader E, Boisson C, Joly P, Stauffer E, Robert M, Girard S, Cibiel A, Gauthier A, Connes P. 2021. Impact of covid-19 on red blood cell rheology. British Journal of Haematology 192:e108–e111. DOI: https://doi.org/10.1111/bjh.17306, PMID: 33410504
Roussel C, Morel A, Dussiot M, Marin M, Colard M, Fricot-Monsinjon A, Martinez A, Chambrion C, Henry B, Casimir M, Volle G, Dépond M, Dokmak S, Paye F, Sauvanet A, Le Van Kim C, Colin Y, Georgeault S, Roingeard P, Spitalnik SL, et al. 2021. Rapid clearance of storage-induced microerythrocytes alters transfusion recovery. Blood 137:2285–2298. DOI: https://doi.org/10.1182/blood.2020008563, PMID: 33657208
Saliba KJ, Ferru I, Kirk K. 2005. Provitamin b5 (pantothenol) inhibits growth of the intraerythrocytic malaria parasite. Antimicrobial Agents and Chemotherapy 49:632–637. DOI: https://doi.org/10.1128/AAC.49.2. 632-637.2005, PMID: 15673744
Schmidt M, Tachon G, Devilliers C, Muller G, Hekimian G, Bréchot N, Merceron S, Luyt CE, Trouillet J-L, Chastre J, Leprince P, Combes A. 2013. Blood oxygenation and decarboxylation determinants during venovenous ECMO for respiratory failure in adults. Intensive Care Medicine 39:838–846. DOI: https://doi.org/ 10.1007/s00134-012-2785-8, PMID: 23291732
Secomb TW. 2017. Blood flow in the microcirculation. Annual Review of Fluid Mechanics 49:443–461. DOI: https://doi.org/10.1146/annurev-fluid-010816-060302
Simionato G, Rabe A, Gallego-Murillo JS, van der Zwaan C, Hoogendijk AJ, van den Biggelaar M, Minetti G, Bogdanova A, Mairbäurl H, Wagner C, Kaestner L, van den Akker E. 2022. In vitro erythropoiesis at different PO2 induces adaptations that are independent of prior systemic exposure to hypoxia. Cells 11:1082. DOI: https://doi.org/10.3390/cells11071082, PMID: 35406648
Tang N, Li D, Wang X, Sun Z. 2020. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. Journal of Thrombosis and Haemostasis 18:844–847. DOI: https:// doi.org/10.1111/jth.14768, PMID: 32073213
Thomas T, Stefanoni D, Dzieciatkowska M, Issaian A, Nemkov T, Hill RC, Francis RO, Hudson KE, Buehler PW, Zimring JC, Hod EA, Hansen KC, Spitalnik SL, D’Alessandro A. 2020a. Evidence of structural protein damage and membrane lipid remodeling in red blood cells from COVID-19 patients. Journal of Proteome Research 19:4455–4469. DOI: https://doi.org/10.1021/acs.jproteome.0c00606, PMID: 33103907
Thomas T, Stefanoni D, Reisz JA, Nemkov T, Bertolone L, Francis RO, Hudson KE, Zimring JC, Hansen KC, Hod EA, Spitalnik SL, D’Alessandro A. 2020b. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight 5:1–16. DOI: https://doi.org/10.1172/jci.insight.140327, PMID: 32559180
Varatharajah N, Rajah S. 2020. Microthrombotic complications of COVID-19 are likely due to embolism of circulating endothelial derived ultralarge von willebrand factor (eulvwf) decorated-platelet strings. Federal Practitioner 37:e1–e2 PMID: 32489244.
Violi F, Ceccarelli G, Loffredo L, Alessandri F, Cipollone F, D’ardes D, D’Ettorre G, Pignatelli P, Venditti M, Mastroianni CM, Pugliese F. 2021. Albumin supplementation dampens hypercoagulability in covid-19: a preliminary report. Thrombosis and Haemostasis 121:102–105. DOI: https://doi.org/10.1055/s-0040-1721486, PMID: 33368057
Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, Hu Y, Tao ZW, Tian JH, Pei YY, Yuan ML, Zhang YL, Dai FH, Liu Y, Wang QM, Zheng JJ, Xu L, Holmes EC, Zhang YZ. 2020. A new coronavirus associated with human respiratory disease in China. Nature 579:265–269. DOI: https://doi.org/10.1038/s41586-020-2008-3, PMID: 32015508