Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. PBMC Isolation and Flow Cytometry
2.3. Monocyte Isolation and Stimulation
2.4. Multiplex Detection of Cytokines
2.5. T Cell Proliferation Assay
2.6. Fluorospot Assay
2.7. RNA Extraction and Nanostring Assay
2.8. ATAC Sequencing
2.9. Statistics
3. Results
3.1. Study Patients
3.2. Phenotype and Function in Acute and Post-COVID-19 Circulating Monocytes
3.3. Monocyte Relationship with Cytokine Environment and SARS-CoV-2-Specific T Cell Response in Acute and Post-COVID-19 Patients
3.4. Inflammation-Resolution Gene Expression in Monocytes from Acute and Post-COVID-19 Patients
3.5. Changes in Chromatin Accessibility of Monocytes from HC, Acute and Post-COVID-19 Patients
3.6. Analysis of Monocyte Markers at Hospital Admission Allows to Identify Acute COVID-19 Patients at High Risk of ICU Requirement and Death
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [Google Scholar] [CrossRef] [Green Version]
- Guan, W.J.; Ni, Z.Y.; Hu, Y.; Liang, W.H.; Ou, C.Q.; He, J.X.; Liu, L.; Shan, H.; Lei, C.L.; Hui, D.S.C.; et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N. Engl. J. Med. 2020, 382, 1708–1720. [Google Scholar] [CrossRef]
- Zhou, F.; Yu, T.; Du, R.; Fan, G.; Liu, Y.; Liu, Z.; Xiang, J.; Wang, Y.; Song, B.; Gu, X.; et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020, 395, 1054–1062. [Google Scholar] [CrossRef]
- Richardson, S.; Hirsch, J.S.; Narasimhan, M.; Crawford, J.M.; McGinn, T.; Davidson, K.W.; The Northwell COVID-19 Research Consortium. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA 2020, 323, 2052–2059. [Google Scholar] [CrossRef] [PubMed]
- Laguna-Goya, R.; Utrero-Rico, A.; Talayero, P.; Lasa-Lazaro, M.; Ramirez-Fernandez, A.; Naranjo, L.; Segura-Tudela, A.; Cabrera-Marante, O.; de Frias, E.R.; Garcia-Garcia, R.; et al. IL-6-based mortality risk model for hospitalized patients with COVID-19. J. Allergy Clin. Immunol. 2020, 146, 799–807. [Google Scholar] [CrossRef] [PubMed]
- Del Valle, D.M.; Kim-Schulze, S.; Huang, H.H.; Beckmann, N.D.; Nirenberg, S.; Wang, B.; Lavin, Y.; Swartz, T.H.; Madduri, D.; Stock, A.; et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat. Med. 2020, 26, 1636–1643. [Google Scholar] [CrossRef] [PubMed]
- Utrero-Rico, A.; Ruiz-Hornillos, J.; Gonzalez-Cuadrado, C.; Rita, C.G.; Almoguera, B.; Minguez, P.; Herrero-Gonzalez, A.; Fernandez-Ruiz, M.; Carretero, O.; Taracido-Fernandez, J.C.; et al. IL-6-based mortality prediction model for COVID-19: Validation and update in multicenter and second wave cohorts. J. Allergy Clin. Immunol. 2021, 147, 1652–1661. [Google Scholar] [CrossRef] [PubMed]
- Ucciferri, C.; Caiazzo, L.; Di Nicola, M.; Borrelli, P.; Pontolillo, M.; Auricchio, A.; Vecchiet, J.; Falasca, K. Parameters associated with diagnosis of COVID-19 in emergency department. Immun. Inflamm. Dis. 2021, 9, 851–861. [Google Scholar] [CrossRef] [PubMed]
- Hadjadj, J.; Yatim, N.; Barnabei, L.; Corneau, A.; Boussier, J.; Smith, N.; Pere, H.; Charbit, B.; Bondet, V.; Chenevier-Gobeaux, C.; et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020, 369, 718–724. [Google Scholar] [CrossRef]
- Blanco-Melo, D.; Nilsson-Payant, B.E.; Liu, W.C.; Uhl, S.; Hoagland, D.; Moller, R.; Jordan, T.X.; Oishi, K.; Panis, M.; Sachs, D.; et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell 2020, 181, 1036–1045. [Google Scholar] [CrossRef]
- Ucciferri, C.; Vecchiet, J.; Falasca, K. Role of monoclonal antibody drugs in the treatment of COVID-19. World J. Clin. Cases 2020, 8, 4280–4285. [Google Scholar] [CrossRef]
- Wilk, A.J.; Rustagi, A.; Zhao, N.Q.; Roque, J.; Martinez-Colon, G.J.; McKechnie, J.L.; Ivison, G.T.; Ranganath, T.; Vergara, R.; Hollis, T.; et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat. Med. 2020, 26, 1070–1076. [Google Scholar] [CrossRef]
- Schulte-Schrepping, J.; Reusch, N.; Paclik, D.; Bassler, K.; Schlickeiser, S.; Zhang, B.; Kramer, B.; Krammer, T.; Brumhard, S.; Bonaguro, L.; et al. Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment. Cell 2020, 182, 1419–1440. [Google Scholar] [CrossRef] [PubMed]
- Sanchez-Cerrillo, I.; Landete, P.; Aldave, B.; Sanchez-Alonso, S.; Sanchez-Azofra, A.; Marcos-Jimenez, A.; Avalos, E.; Alcaraz-Serna, A.; de Los Santos, I.; Mateu-Albero, T.; et al. COVID-19 severity associates with pulmonary redistribution of CD1c+ DCs and inflammatory transitional and nonclassical monocytes. J. Clin. Investig. 2020, 130, 6290–6300. [Google Scholar] [CrossRef]
- Giamarellos-Bourboulis, E.J.; Netea, M.G.; Rovina, N.; Akinosoglou, K.; Antoniadou, A.; Antonakos, N.; Damoraki, G.; Gkavogianni, T.; Adami, M.E.; Katsaounou, P.; et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe 2020, 27, 992–1000. [Google Scholar] [CrossRef] [PubMed]
- Liao, M.; Liu, Y.; Yuan, J.; Wen, Y.; Xu, G.; Zhao, J.; Cheng, L.; Li, J.; Wang, X.; Wang, F.; et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat. Med. 2020, 26, 842–844. [Google Scholar] [CrossRef]
- Grant, R.A.; Morales-Nebreda, L.; Markov, N.S.; Swaminathan, S.; Querrey, M.; Guzman, E.R.; Abbott, D.A.; Donnelly, H.K.; Donayre, A.; Goldberg, I.A.; et al. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. Nature 2021, 590, 635–641. [Google Scholar] [CrossRef]
- Xu, G.; Qi, F.; Li, H.; Yang, Q.; Wang, H.; Wang, X.; Liu, X.; Zhao, J.; Liao, X.; Liu, Y.; et al. The differential immune responses to COVID-19 in peripheral and lung revealed by single-cell RNA sequencing. Cell Discov. 2020, 6, 73. [Google Scholar] [CrossRef] [PubMed]
- Huang, C.; Huang, L.; Wang, Y.; Li, X.; Ren, L.; Gu, X.; Kang, L.; Guo, L.; Liu, M.; Zhou, X.; et al. 6-month consequences of COVID-19 in patients discharged from hospital: A cohort study. Lancet 2021, 397, 220–232. [Google Scholar] [CrossRef]
- Sudre, C.H.; Murray, B.; Varsavsky, T.; Graham, M.S.; Penfold, R.S.; Bowyer, R.C.; Pujol, J.C.; Klaser, K.; Antonelli, M.; Canas, L.S.; et al. Attributes and predictors of long COVID. Nat. Med. 2021, 27, 626–631. [Google Scholar] [CrossRef]
- Nalbandian, A.; Sehgal, K.; Gupta, A.; Madhavan, M.V.; McGroder, C.; Stevens, J.S.; Cook, J.R.; Nordvig, A.S.; Shalev, D.; Sehrawat, T.S.; et al. Post-acute COVID-19 syndrome. Nat. Med. 2021, 27, 601–615. [Google Scholar] [CrossRef]
- Moreno-Perez, O.; Merino, E.; Leon-Ramirez, J.M.; Andres, M.; Ramos, J.M.; Arenas-Jimenez, J.; Asensio, S.; Sanchez, R.; Ruiz-Torregrosa, P.; Galan, I.; et al. Post-acute COVID-19 syndrome. Incidence and risk factors: A Mediterranean cohort study. J. Infect. 2021, 82, 378–383. [Google Scholar] [CrossRef]
- Oronsky, B.; Larson, C.; Hammond, T.C.; Oronsky, A.; Kesari, S.; Lybeck, M.; Reid, T.R. A Review of Persistent Post-COVID Syndrome (PPCS). Clin. Rev. Allergy Immunol. 2021. [Google Scholar] [CrossRef] [PubMed]
- Zhang, D.; Guo, R.; Lei, L.; Liu, H.; Wang, Y.; Wang, Y.; Qian, H.; Dai, T.; Zhang, T.; Lai, Y.; et al. Frontline Science: COVID-19 infection induces readily detectable morphologic and inflammation-related phenotypic changes in peripheral blood monocytes. J. Leukoc. Biol. 2021, 109, 13–22. [Google Scholar] [CrossRef] [PubMed]
- Kahn, R.; Schmidt, T.; Golestani, K.; Mossberg, A.; Gullstrand, B.; Bengtsson, A.A.; Kahn, F. Mismatch between circulating cytokines and spontaneous cytokine production by leukocytes in hyperinflammatory COVID-19. J. Leukoc. Biol. 2021, 109, 115–120. [Google Scholar] [CrossRef] [PubMed]
- Tajima, K.; Matsuda, S.; Yae, T.; Drapkin, B.J.; Morris, R.; Boukhali, M.; Niederhoffer, K.; Comaills, V.; Dubash, T.; Nieman, L.; et al. SETD1A protects from senescence through regulation of the mitotic gene expression program. Nat. Commun. 2019, 10, 2854. [Google Scholar] [CrossRef]
- Lukasova, E.; Kovar ik, A.; Bac ikova, A.; Falk, M.; Kozubek, S. Loss of lamin B receptor is necessary to induce cellular senescence. Biochem. J. 2017, 474, 281–300. [Google Scholar] [CrossRef]
- Liu, Y.; Yan, L.M.; Wan, L.; Xiang, T.X.; Le, A.; Liu, J.M.; Peiris, M.; Poon, L.L.M.; Zhang, W. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect. Dis. 2020, 20, 656–657. [Google Scholar] [CrossRef] [Green Version]
- Zheng, S.; Fan, J.; Yu, F.; Feng, B.; Lou, B.; Zou, Q.; Xie, G.; Lin, S.; Wang, R.; Yang, X.; et al. Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January–March 2020: Retrospective cohort study. BMJ 2020, 369, m1443. [Google Scholar] [CrossRef] [Green Version]
- Amodio, E.; Pipitone, R.M.; Grimaudo, S.; Immordino, P.; Maida, C.M.; Prestileo, T.; Restivo, V.; Tramuto, F.; Vitale, F.; Craxi, A.; et al. SARS-CoV-2 Viral Load, IFNlambda Polymorphisms and the Course of COVID-19: An Observational Study. J. Clin. Med. 2020, 9, 3315. [Google Scholar] [CrossRef]
- Nappi, F.; Iervolino, A.; Avtaar Singh, S.S. COVID-19 Pathogenesis: From Molecular Pathway to Vaccine Administration. Biomedicines 2021, 9, 903. [Google Scholar] [CrossRef] [PubMed]
- Bost, P.; De Sanctis, F.; Cane, S.; Ugel, S.; Donadello, K.; Castellucci, M.; Eyal, D.; Fiore, A.; Anselmi, C.; Barouni, R.M.; et al. Deciphering the state of immune silence in fatal COVID-19 patients. Nat. Commun. 2021, 12, 1428. [Google Scholar] [CrossRef] [PubMed]
- Kvedaraite, E.; Hertwig, L.; Sinha, I.; Ponzetta, A.; Hed Myrberg, I.; Lourda, M.; Dzidic, M.; Akber, M.; Klingstrom, J.; Folkesson, E.; et al. Major alterations in the mononuclear phagocyte landscape associated with COVID-19 severity. Proc. Natl. Acad. Sci. USA 2021, 118. [Google Scholar] [CrossRef]
- Knoll, R.; Schultze, J.L.; Schulte-Schrepping, J. Monocytes and Macrophages in COVID-19. Front. Immunol. 2021, 12, 720109. [Google Scholar] [CrossRef] [PubMed]
- Gille-Johnson, P.; Smedman, C.; Gudmundsdotter, L.; Somell, A.; Nihlmark, K.; Paulie, S.; Andersson, J.; Gardlund, B. Circulating monocytes are not the major source of plasma cytokines in patients with sepsis. Shock 2012, 38, 577–583. [Google Scholar] [CrossRef] [Green Version]
- Angus, D.C.; van der Poll, T. Severe sepsis and septic shock. N. Engl. J. Med. 2013, 369, 840–851. [Google Scholar] [CrossRef]
- Mehta, P.; McAuley, D.F.; Brown, M.; Sanchez, E.; Tattersall, R.S.; Manson, J.J.; Hlh Across Speciality Collaboration, U.K. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020, 395, 1033–1034. [Google Scholar] [CrossRef]
- Wen, W.; Su, W.; Tang, H.; Le, W.; Zhang, X.; Zheng, Y.; Liu, X.; Xie, L.; Li, J.; Ye, J.; et al. Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing. Cell Discov. 2020, 6, 31. [Google Scholar] [CrossRef]
- Zhou, Y.; Fu, B.; Zheng, X.; Wang, D.; Zhao, C.; qi, Y.; Sun, R.; Tian, Z.; Xu, X.; Wei, H. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients. Natl. Sci. Rev. 2020, 7, 998–1002. [Google Scholar] [CrossRef] [Green Version]
- Yu, R.Y.; Wang, X.; Pixley, F.J.; Yu, J.J.; Dent, A.L.; Broxmeyer, H.E.; Stanley, E.R.; Ye, B.H. BCL-6 negatively regulates macrophage proliferation by suppressing autocrine IL-6 production. Blood 2005, 105, 1777–1784. [Google Scholar] [CrossRef] [Green Version]
- Barish, G.D.; Yu, R.T.; Karunasiri, M.; Ocampo, C.B.; Dixon, J.; Benner, C.; Dent, A.L.; Tangirala, R.K.; Evans, R.M. Bcl-6 and NF-kappaB cistromes mediate opposing regulation of the innate immune response. Genes Dev. 2010, 24, 2760–2765. [Google Scholar] [CrossRef] [Green Version]
- Toney, L.M.; Cattoretti, G.; Graf, J.A.; Merghoub, T.; Pandolfi, P.P.; Dalla-Favera, R.; Ye, B.H.; Dent, A.L. BCL-6 regulates chemokine gene transcription in macrophages. Nat. Immunol. 2000, 1, 214–220. [Google Scholar] [CrossRef]
- Cuevas, V.D.; Anta, L.; Samaniego, R.; Orta-Zavalza, E.; de la Rosa, J.V.; Baujat, G.; Dominguez-Soto, A.; Sanchez-Mateos, P.; Escribese, M.M.; Castrillo, A.; et al. MAFB Determines Human Macrophage Anti-Inflammatory Polarization: Relevance for the Pathogenic Mechanisms Operating in Multicentric Carpotarsal Osteolysis. J. Immunol. 2017, 198, 2070–2081. [Google Scholar] [CrossRef]
- Kang, K.; Park, S.H.; Chen, J.; Qiao, Y.; Giannopoulou, E.; Berg, K.; Hanidu, A.; Li, J.; Nabozny, G.; Kang, K.; et al. Interferon-gamma Represses M2 Gene Expression in Human Macrophages by Disassembling Enhancers Bound by the Transcription Factor MAF. Immunity 2017, 47, 235–250. [Google Scholar] [CrossRef]
- Xu, Y.; Meng, C.; Liu, G.; Yang, D.; Fu, L.; Zhang, M.; Zhang, Z.; Xia, H.; Yao, S.; Zhang, S. Classically Activated Macrophages Protect against Lipopolysaccharide-induced Acute Lung Injury by Expressing Amphiregulin in Mice. Anesthesiology 2016, 124, 1086–1099. [Google Scholar] [CrossRef] [PubMed]
- Guo, C.; Li, B.; Ma, H.; Wang, X.; Cai, P.; Yu, Q.; Zhu, L.; Jin, L.; Jiang, C.; Fang, J.; et al. Single-cell analysis of two severe COVID-19 patients reveals a monocyte-associated and tocilizumab-responding cytokine storm. Nat. Commun. 2020, 11, 3924. [Google Scholar] [CrossRef] [PubMed]
- Falck-Jones, S.; Vangeti, S.; Yu, M.; Falck-Jones, R.; Cagigi, A.; Badolati, I.; Osterberg, B.; Lautenbach, M.J.; Ahlberg, E.; Lin, A.; et al. Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity. J. Clin. Investig. 2021, 131. [Google Scholar] [CrossRef] [PubMed]
- Agrati, C.; Sacchi, A.; Bordoni, V.; Cimini, E.; Notari, S.; Grassi, G.; Casetti, R.; Tartaglia, E.; Lalle, E.; D’Abramo, A.; et al. Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19). Cell Death Differ. 2020, 27, 3196–3207. [Google Scholar] [CrossRef] [PubMed]
- Boumaza, A.; Gay, L.; Mezouar, S.; Bestion, E.; Diallo, A.B.; Michel, M.; Desnues, B.; Raoult, D.; La Scola, B.; Halfon, P.; et al. Monocytes and macrophages, targets of SARS-CoV-2: The clue for Covid-19 immunoparalysis. J. Infect. Dis. 2021. [Google Scholar] [CrossRef]
- Muus, C.; Luecken, M.D.; Eraslan, G.; Sikkema, L.; Waghray, A.; Heimberg, G.; Kobayashi, Y.; Vaishnav, E.D.; Subramanian, A.; Smillie, C.; et al. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nat. Med. 2021, 27, 546–559. [Google Scholar] [CrossRef] [PubMed]
- Xiang, Q.; Feng, Z.; Diao, B.; Tu, C.; Qiao, Q.; Yang, H.; Zhang, Y.; Wang, G.; Wang, H.; Wang, C.; et al. SARS-CoV-2 Induces Lymphocytopenia by Promoting Inflammation and Decimates Secondary Lymphoid Organs. Front. Immunol. 2021, 12, 661052. [Google Scholar] [CrossRef]
- Zhou, L.; Niu, Z.; Jiang, X.; Zhang, Z.; Zheng, Y.; Wang, Z.; Zhu, Y.; Gao, L.; Huang, H.; Wang, X.; et al. SARS-CoV-2 Targets by the pscRNA Profiling of ACE2, TMPRSS2 and Furin Proteases. iScience 2020, 23, 101744. [Google Scholar] [CrossRef]
- Reyes, M.; Filbin, M.R.; Bhattacharyya, R.P.; Sonny, A.; Mehta, A.; Billman, K.; Kays, K.R.; Pinilla-Vera, M.; Benson, M.E.; Cosimi, L.A.; et al. Plasma from patients with bacterial sepsis or severe COVID-19 induces suppressive myeloid cell production from hematopoietic progenitors in vitro. Sci. Transl. Med. 2021, 13. [Google Scholar] [CrossRef]
- Bekkering, S.; Dominguez-Andres, J.; Joosten, L.A.B.; Riksen, N.P.; Netea, M.G. Trained Immunity: Reprogramming Innate Immunity in Health and Disease. Annu. Rev. Immunol. 2021, 39, 667–693. [Google Scholar] [CrossRef]
- En, A.; Takauji, Y.; Ayusawa, D.; Fujii, M. The role of lamin B receptor in the regulation of senescence-associated secretory phenotype (SASP). Exp. Cell Res. 2020, 390, 111927. [Google Scholar] [CrossRef] [PubMed]
- Cillo, A.R.; Somasundaram, A.; Shan, F.; Cardello, C.; Workman, C.J.; Kitsios, G.D.; Ruffin, A.; Kunning, S.; Lampenfeld, C.; Onkar, S.; et al. Bifurcated monocyte states are predictive of mortality in severe COVID-19. bioRxiv 2021. [Google Scholar] [CrossRef]
- Yao, C.; Bora, S.A.; Parimon, T.; Zaman, T.; Friedman, O.A.; Palatinus, J.A.; Surapaneni, N.S.; Matusov, Y.P.; Chiang, G.C.; Kassar, A.G.; et al. Cell-type-specific immune dysregulation in severely ill COVID-19 patients. Cell Rep. 2021, 34, 108943. [Google Scholar] [CrossRef] [PubMed]
- Feng, H.; Zhang, Y.B.; Gui, J.F.; Lemon, S.M.; Yamane, D. Interferon regulatory factor 1 (IRF1) and anti-pathogen innate immune responses. PLoS Pathog. 2021, 17, e1009220. [Google Scholar] [CrossRef]
- Forero, A.; Ozarkar, S.; Li, H.; Lee, C.H.; Hemann, E.A.; Nadjsombati, M.S.; Hendricks, M.R.; So, L.; Green, R.; Roy, C.N.; et al. Differential Activation of the Transcription Factor IRF1 Underlies the Distinct Immune Responses Elicited by Type I and Type III Interferons. Immunity 2019, 51, 451–464. [Google Scholar] [CrossRef] [PubMed]
- Carlin, A.F.; Plummer, E.M.; Vizcarra, E.A.; Sheets, N.; Joo, Y.; Tang, W.; Day, J.; Greenbaum, J.; Glass, C.K.; Diamond, M.S.; et al. An IRF-3-, IRF-5-, and IRF-7-Independent Pathway of Dengue Viral Resistance Utilizes IRF-1 to Stimulate Type I and II Interferon Responses. Cell Rep. 2017, 21, 1600–1612. [Google Scholar] [CrossRef] [Green Version]
- Negishi, H.; Fujita, Y.; Yanai, H.; Sakaguchi, S.; Ouyang, X.; Shinohara, M.; Takayanagi, H.; Ohba, Y.; Taniguchi, T.; Honda, K. Evidence for licensing of IFN-gamma-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program. Proc. Natl. Acad. Sci. USA 2006, 103, 15136–15141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Utrero-Rico, A.; González-Cuadrado, C.; Chivite-Lacaba, M.; Cabrera-Marante, O.; Laguna-Goya, R.; Almendro-Vazquez, P.; Díaz-Pedroche, C.; Ruiz-Ruigómez, M.; Lalueza, A.; Folgueira, M.D.; et al. Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery. Biomedicines 2021, 9, 1253. https://doi.org/10.3390/biomedicines9091253
Utrero-Rico A, González-Cuadrado C, Chivite-Lacaba M, Cabrera-Marante O, Laguna-Goya R, Almendro-Vazquez P, Díaz-Pedroche C, Ruiz-Ruigómez M, Lalueza A, Folgueira MD, et al. Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery. Biomedicines. 2021; 9(9):1253. https://doi.org/10.3390/biomedicines9091253
Chicago/Turabian StyleUtrero-Rico, Alberto, Cecilia González-Cuadrado, Marta Chivite-Lacaba, Oscar Cabrera-Marante, Rocío Laguna-Goya, Patricia Almendro-Vazquez, Carmen Díaz-Pedroche, María Ruiz-Ruigómez, Antonio Lalueza, María Dolores Folgueira, and et al. 2021. "Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery" Biomedicines 9, no. 9: 1253. https://doi.org/10.3390/biomedicines9091253