Linking COVID-19 and Heme-Driven Pathophysiologies: A Combined Computational–Experimental Approach
Abstract
:1. Introduction
2. Materials and Methods
2.1. Modeling the Interplay between SARS-CoV-2 and Heme
2.2. Screening for Potential HBMs in COVID-19-Related Proteins
2.3. HBM-Peptide Synthesis, Purification and Heme-Binding Analysis
3. Results
3.1. Effects of Heme and COVID-19 Intersect at Inflammation
3.2. Heme-Binding Ability of Proteins of SARS-CoV-2 and Host Cells
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Cucinotta, D.; Vanelli, M. WHO declares COVID-19 a pandemic. Acta Biomed. 2020, 91, 157–160. [Google Scholar]
- 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]
- Ye, Q.; Wang, B.; Mao, J. The pathogenesis and treatment of the Cytokine Storm in COVID-19. J. Infect. 2020, 80, 607–613. [Google Scholar] [CrossRef]
- Ragab, D.; Salah Eldin, H.; Taeimah, M.; Khattab, R.; Salem, R. The COVID-19 cytokine storm: What we know so far. Front. Immunol. 2020, 11, 1446. [Google Scholar] [CrossRef] [PubMed]
- Hanff, T.C.; Harhay, M.O.; Brown, T.S.; Cohen, J.B.; Mohareb, A.M. Is there an association between COVID-19 mortality and the renin-angiotensin system?—A call for epidemiologic investigations. Clin. Infect. Dis. 2020, 71, 870–874. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mascolo, A.; Scavone, C.; Rafaniello, C.; Ferrajolo, C.; Racagni, G.; Berrino, L.; Paolisso, G.; Rossi, F.; Capuano, A. Renin-angiotensin system and coronavirus disease 2019: A narrative review. Front. Cardiovasc. Med. 2020, 7, 143. [Google Scholar] [CrossRef] [PubMed]
- Yi, C.; Sun, X.; Ye, J.; Ding, L.; Liu, M.; Yang, Z.; Lu, X.; Zhang, Y.; Ma, L.; Gu, W.; et al. Key residues of the receptor binding motif in the spike protein of SARS-CoV-2 that interact with ACE2 and neutralizing antibodies. Cell. Mol. Immunol. 2020, 17, 621–630. [Google Scholar] [CrossRef] [PubMed]
- Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.-H.; Nitsche, A.; et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020, 181, 271–280.e8. [Google Scholar] [CrossRef] [PubMed]
- Ali, A.; Vijayan, R. Dynamics of the ACE2–SARS-CoV-2/SARS-CoV spike protein interface reveal unique mechanisms. Sci. Rep. 2020, 10, 14214. [Google Scholar] [CrossRef] [PubMed]
- Xue, X.; Shi, J.; Xu, H.; Qin, Y.; Yang, Z.; Feng, S.; Liu, D.; Jian, L.; Hua, L.; Wang, Y.; et al. Dynamics of binding ability prediction between spike protein and human ACE2 reveals the adaptive strategy of SARS-CoV-2 in humans. Sci. Rep. 2021, 11, 3187. [Google Scholar] [CrossRef]
- Ren, X. Analysis of ACE2 in polarized epithelial cells: Surface expression and function as receptor for severe acute respiratory syndrome-associated coronavirus. J. Gen. Virol. 2006, 87, 1691–1695. [Google Scholar] [CrossRef] [PubMed]
- Wu, K.; Peng, G.; Wilken, M.; Geraghty, R.J.; Li, F. Mechanisms of host receptor adaptation by severe acute respiratory syndrome coronavirus. J. Biol. Chem. 2012, 287, 8904–8911. [Google Scholar] [CrossRef] [Green Version]
- Zhai, X.; Sun, J.; Yan, Z.; Zhang, J.; Zhao, J.; Zhao, Z.; Gao, Q.; He, W.-T.; Veit, M.; Su, S. Comparison of severe acute respiratory syndrome coronavirus 2 spike protein binding to ACE2 receptors from human, pets, farm animals, and putative intermediate hosts. J. Virol. 2020, 94, e00831-20. [Google Scholar] [CrossRef] [PubMed]
- Bianchi, M.; Benvenuto, D.; Giovanetti, M.; Angeletti, S.; Ciccozzi, M.; Pascarella, S. Sars-CoV-2 envelope and membrane proteins: Structural differences linked to virus characteristics? Biomed. Res. Int. 2020, 2020, 1–6. [Google Scholar] [CrossRef] [PubMed]
- Boson, B.; Legros, V.; Zhou, B.; Siret, E.; Mathieu, C.; Cosset, F.-L.; Lavillette, D.; Denolly, S. The SARS-CoV-2 envelope and membrane proteins modulate maturation and retention of the spike protein, allowing assembly of virus-like particles. J. Biol. Chem. 2021, 296, 100111. [Google Scholar] [CrossRef]
- Fielding, B.C.; Gunalan, V.; Tan, T.H.P.; Chou, C.-F.; Shen, S.; Khan, S.; Lim, S.G.; Hong, W.; Tan, Y.-J. Severe acute respiratory syndrome coronavirus protein 7a interacts with hSGT. Biochem. Biophys. Res. Commun. 2006, 343, 1201–1208. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kwon, S.; Kim, E.; Jung, Y.S.; Jang, J.S.; Cho, N. Post-donation COVID-19 identification in blood donors. Vox Sang. 2020, 115, 601–602. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rosenthal, S.H.; Kagan, R.M.; Gerasimova, A.; Anderson, B.; Grover, D.; Hua, M.; Liu, Y.; Owen, R.; Lacbawan, F. Identification of eight SARS-CoV-2 ORF7a deletion variants in 2726 clinical specimens. bioRxiv 2020. [Google Scholar] [CrossRef]
- Zhou, Z.; Huang, C.; Zhou, Z.; Huang, Z.; Su, L.; Kang, S.; Chen, X.; Chen, Q.; He, S.; Rong, X.; et al. Structural insight reveals SARS-CoV-2 Orf7a as an immunomodulating factor for human CD14+ monocytes. SSRN Electron. J. 2020, 24, 102187. [Google Scholar]
- Chen, N.; Zhou, M.; Dong, X.; Qu, J.; Gong, F.; Han, Y.; Qiu, Y.; Wang, J.; Liu, Y.; Wei, Y.; et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020, 395, 507–513. [Google Scholar] [CrossRef] [Green Version]
- Guan, W.; Ni, Z.; Hu, Y.; Liang, W.; Ou, C.; He, J.; Liu, L.; Shan, H.; Lei, C.; 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] [PubMed]
- Han, H.; Yang, L.; Liu, R.; Liu, F.; Wu, K.; Li, J.; Liu, X.; Zhu, C. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin. Chem. Lab. Med. 2020, 58, 1116–1120. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Latz, C.A.; DeCarlo, C.; Boitano, L.; Png, C.Y.M.; Patell, R.; Conrad, M.F.; Eagleton, M.; Dua, A. Blood type and outcomes in patients with COVID-19. Ann. Hematol. 2020, 99, 2113–2118. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Wang, X.; Chen, J.; Cai, Y.; Deng, A.; Yang, M. Association between ABO blood groups and risk of SARS-CoV-2 pneumonia. Br. J. Haematol. 2020, 190, 24–27. [Google Scholar] [CrossRef] [PubMed]
- Wu, B.-B.; Gu, D.-Z.; Yu, J.-N.; Yang, J.; Shen, W.-Q. Association between ABO blood groups and COVID-19 infection, severity and demise: A systematic review and meta-analysis. Infect. Genet. Evol. 2020, 84, 104485. [Google Scholar] [CrossRef] [PubMed]
- Zhao, J.; Yang, Y.; Huang, H.; Li, D.; Gu, D.; Lu, X.; Zhang, Z.; Liu, L.; Liu, T.; Liu, Y.; et al. Relationship between the ABO blood group and the coronavirus disease 2019 (COVID-19) susceptibility. Clin. Infect. Dis. 2020, ciaa1150. [Google Scholar] [CrossRef]
- Risitano, A.M.; Mastellos, D.C.; Huber-Lang, M.; Yancopoulou, D.; Garlanda, C.; Ciceri, F.; Lambris, J.D. Complement as a target in COVID-19? Nat. Rev. Immunol. 2020, 20, 343–344. [Google Scholar] [CrossRef] [Green Version]
- Wang, R.; Pan, M.; Zhang, X.; Han, M.; Fan, X.; Zhao, F.; Miao, M.; Xu, J.; Guan, M.; Deng, X.; et al. Epidemiological and clinical features of 125 Hospitalized Patients with COVID-19 in Fuyang, Anhui, China. Int. J. Infect. Dis. 2020, 95, 421–428. [Google Scholar] [CrossRef]
- Whetton, A.D.; Preston, G.W.; Abubeker, S.; Geifman, N. Proteomics and informatics for understanding phases and identifying biomarkers in COVID-19 disease. J. Proteome Res. 2020, 19, 4219–4232. [Google Scholar] [CrossRef]
- Zhang, X.; Cai, H.; Hu, J.; Lian, J.; Gu, J.; Zhang, S.; Ye, C.; Lu, Y.; Jin, C.; Yu, G.; et al. Epidemiological, clinical characteristics of cases of SARS-CoV-2 infection with abnormal imaging findings. Int. J. Infect. Dis. 2020, 94, 81–87. [Google Scholar] [CrossRef] [PubMed]
- Tang, N.; Li, D.; Wang, X.; Sun, Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J. Thromb. Haemost. 2020, 18, 844–847. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ji, H.-L.; Zhao, R.; Matalon, S.; Matthay, M.A. Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility. Physiol. Rev. 2020, 100, 1065–1075. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Grobler, C.; Maphumulo, S.C.; Grobbelaar, L.M.; Bredenkamp, J.C.; Laubscher, G.J.; Lourens, P.J.; Steenkamp, J.; Kell, D.B.; Pretorius, E. Covid-19: The rollercoaster of fibrin(ogen), D-Dimer, von Willebrand factor, P-selectin and their interactions with endothelial cells, platelets and erythrocytes. Int. J. Mol. Sci. 2020, 21, 5168. [Google Scholar] [CrossRef] [PubMed]
- Giannis, D.; Ziogas, I.A.; Gianni, P. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J. Clin. Virol. 2020, 127, 104362. [Google Scholar] [CrossRef] [PubMed]
- Manne, B.K.; Denorme, F.; Middleton, E.A.; Portier, I.; Rowley, J.W.; Stubben, C.; Petrey, A.C.; Tolley, N.D.; Guo, L.; Cody, M.; et al. Platelet gene expression and function in patients with COVID-19. Blood 2020, 136, 1317–1329. [Google Scholar] [CrossRef] [PubMed]
- Leppkes, M.; Knopf, J.; Naschberger, E.; Lindemann, A.; Singh, J.; Herrmann, I.; Stürzl, M.; Staats, L.; Mahajan, A.; Schauer, C.; et al. Vascular occlusion by neutrophil extracellular traps in COVID-19. EBioMedicine 2020, 58, 102925. [Google Scholar] [CrossRef] [PubMed]
- Zuo, Y.; Warnock, M.; Harbaugh, A.; Yalavarthi, S.; Gockman, K.; Zuo, M.; Madison, J.A.; Knight, J.S.; Kanthi, Y.; Lawrence, D.A. Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients. Sci. Rep. 2021, 11, 1580. [Google Scholar] [CrossRef] [PubMed]
- Yang, X.; Yu, Y.; Xu, J.; Shu, H.; Xia, J.; Liu, H.; Wu, Y.; Zhang, L.; Yu, Z.; Fang, M.; et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir. Med. 2020, 8, 475–481. [Google Scholar] [CrossRef] [Green Version]
- Dutra, F.F.; Bozza, M.T. Heme on innate immunity and inflammation. Front. Pharmacol. 2014, 5, 115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kühl, T.; Imhof, D. Regulatory Fe (II/III) heme: The reconstruction of a molecule’s biography. ChemBioChem 2014, 15, 2024–2035. [Google Scholar] [CrossRef] [PubMed]
- Roumenina, L.T.; Rayes, J.; Lacroix-Desmazes, S.; Dimitrov, J.D. Heme: Modulator of plasma systems in hemolytic diseases. Trends Mol. Med. 2016, 22, 200–213. [Google Scholar] [CrossRef]
- Humayun, F.; Domingo-Fernández, D.; Paul George, A.A.; Hopp, M.-T.; Syllwasschy, B.F.; Detzel, M.S.; Hoyt, C.T.; Hofmann-Apitius, M.; Imhof, D. A computational approach for mapping heme biology in the context of hemolytic disorders. Front. Bioeng. Biotechnol. 2020, 8, 74. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hopp, M.-T.; Imhof, D. Linking labile heme with thrombosis. J. Clin. Med. 2021, 10, 427. [Google Scholar] [CrossRef]
- Ascenzi, P.; Bocedi, A.; Visca, P.; Altruda, F.; Tolosano, E.; Beringhelli, T.; Fasano, M. Hemoglobin and heme scavenging. IUBMB Life 2005, 57, 749–759. [Google Scholar] [CrossRef] [PubMed]
- Gouveia, Z.; Carlos, A.R.; Yuan, X.; Aires-da-Silva, F.; Stocker, R.; Maghzal, G.J.; Leal, S.S.; Gomes, C.M.; Todorovic, S.; Iranzo, O.; et al. Characterization of plasma labile heme in hemolytic conditions. FEBS J. 2017, 284, 3278–3301. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chiabrando, D.; Vinchi, F.; Fiorito, V.; Mercurio, S.; Tolosano, E. Heme in pathophysiology: A matter of scavenging, metabolism and trafficking across cell membranes. Front. Pharmacol. 2014, 5, 61. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Martins, R.; Maier, J.; Gorki, A.-D.; Huber, K.V.M.; Sharif, O.; Starkl, P.; Saluzzo, S.; Quattrone, F.; Gawish, R.; Lakovits, K.; et al. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions. Nat. Immunol. 2016, 17, 1361–1372. [Google Scholar] [CrossRef]
- Kupke, T.; Klare, J.P.; Brügger, B. Heme binding of transmembrane signaling proteins undergoing regulated intramembrane proteolysis. Commun. Biol. 2020, 3, 73. [Google Scholar] [CrossRef]
- Janciauskiene, S.; Vijayan, V.; Immenschuh, S. TLR4 signaling by heme and the role of heme-binding blood proteins. Front. Immunol. 2020, 11, 1964. [Google Scholar] [CrossRef]
- Kodamullil, A.T.; Younesi, E.; Naz, M.; Bagewadi, S.; Hofmann-Apitius, M. Computable cause-and-effect models of healthy and Alzheimer’s disease states and their mechanistic differential analysis. Alzheimer’s Dement. 2015, 11, 1329–1339. [Google Scholar] [CrossRef]
- Karki, R.; Kodamullil, A.T.; Hofmann-Apitius, M. Comorbidity analysis between Alzheimer’s Disease and type 2 diabetes mellitus (T2DM) based on shared pathways and the role of T2DM drugs. J. Alzheimer’s Dis. 2017, 60, 721–731. [Google Scholar] [CrossRef] [Green Version]
- Emon, M.A.E.K.; Kodamullil, A.T.; Karki, R.; Younesi, E.; Hofmann-Apitius, M. Using Drugs as Molecular Probes: A Computational Chemical Biology Approach in Neurodegenerative Diseases. J. Alzheimer’s Dis. 2017, 56, 677–686. [Google Scholar] [CrossRef] [Green Version]
- Karki, R.; Madan, S.; Gadiya, Y.; Domingo-Fernández, D.; Kodamullil, A.T.; Hofmann-Apitius, M. Data-driven modeling of knowledge assemblies in understanding comorbidity between type 2 diabetes mellitus and Alzheimer’s Disease. J. Alzheimer’s Dis. 2020, 78, 87–95. [Google Scholar] [CrossRef]
- Domingo-Fernández, D.; Baksi, S.; Schultz, B.; Gadiya, Y.; Karki, R.; Raschka, T.; Ebeling, C.; Hofmann-Apitius, M.; Kodamullil, A.T. COVID-19 Knowledge Graph: A computable, multi-modal, cause-and-effect knowledge model of COVID-19 pathophysiology. Bioinformatics 2020, btaa834. [Google Scholar] [CrossRef] [PubMed]
- Paul George, A.A.; Lacerda, M.; Syllwasschy, B.F.; Hopp, M.-T.; Wißbrock, A.; Imhof, D. HeMoQuest: A webserver for qualitative prediction of transient heme binding to protein motifs. BMC Bioinform. 2020, 21, 124. [Google Scholar] [CrossRef] [PubMed]
- Hoyt, C.T.; Konotopez, A.; Ebeling, C. PyBEL: A computational framework for Biological Expression Language. Bioinformatics 2018, 34, 703–704. [Google Scholar] [CrossRef] [Green Version]
- Fisher, R.A. Statistical methods for research workers. In Breakthroughs in Statistics; Springer: New York, NY, USA, 1992; pp. 66–70. [Google Scholar]
- Blanco-Melo, D.; Nilsson-Payant, B.E.; Liu, W.-C.; Uhl, S.; Hoagland, D.; Møller, 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.e9. [Google Scholar] [CrossRef] [PubMed]
- 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]
- Kühl, T.; Sahoo, N.; Nikolajski, M.; Schlott, B.; Heinemann, S.H.; Imhof, D.; Kühl, T.; Heinemann, S.H.; Schlott, B.; Imhof, D.; et al. Determination of Hemin-Binding Characteristics of Proteins by a Combinatorial Peptide Library Approach. ChemBioChem 2011, 12, 2846–2855. [Google Scholar] [CrossRef]
- Kühl, T.; Wißbrock, A.; Goradia, N.; Sahoo, N.; Galler, K.; Neugebauer, U.; Popp, J.; Heinemann, S.H.; Ohlenschläger, O.; Imhof, D. Analysis of Fe(III) heme binding to cysteine-containing heme-regulatory motifs in proteins. ACS Chem. Biol. 2013, 8, 1785–1793. [Google Scholar] [CrossRef]
- Pîrnău, A.; Bogdan, M. Investigation of the interaction between naproxen and human serum albumin. Rom. J. Biophys. 2008, 18, 49–55. [Google Scholar]
- Chen, T.; Wu, D.; Chen, H.; Yan, W.; Yang, D.; Chen, G.; Ma, K.; Xu, D.; Yu, H.; Wang, H.; et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: Retrospective study. BMJ 2020, 368, m1091. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Young, B.E.; Ong, S.W.X.; Kalimuddin, S.; Low, J.G.; Tan, S.Y.; Loh, J.; Ng, O.-T.; Marimuthu, K.; Ang, L.W.; Mak, T.M.; et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. J. Amer. Med. Assoc. 2020, 323, 1488–1494. [Google Scholar] [CrossRef] [Green Version]
- Litalien, C.; Proulx, F.; Mariscalco, M.M.; Robitaille, P.; Turgeon, J.P.; Orrbine, E.; Rowe, P.C.; McLaine, P.N.; Seidman, E. Circulating inflammatory cytokine levels in hemolytic uremic syndrome. Pediatr. Nephrol. 1999, 13, 840–845. [Google Scholar] [CrossRef] [PubMed]
- Barcellini, W.; Fattizzo, B. Clinical applications of hemolytic markers in the differential diagnosis and management of hemolytic anemia. Dis. Markers 2015, 2015, 635670. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Aggarwal, S.; Lazrak, A.; Ahmad, I.; Yu, Z.; Bryant, A.; Mobley, J.A.; Ford, D.A.; Matalon, S. Reactive species generated by heme impair alveolar epithelial sodium channel function in acute respiratory distress syndrome. Redox Biol. 2020, 36, 101592. [Google Scholar] [CrossRef] [PubMed]
- Lecerf, M.; Scheel, T.; Pashov, A.D.; Jarossay, A.; Ohayon, D.; Planchais, C.; Mesnage, S.; Berek, C.; Kaveri, S.V.; Lacroix-Desmazes, S.; et al. Prevalence and gene characteristics of antibodies with cofactor-induced HIV-1 specificity. J. Biol. Chem. 2015, 290, 5203–5213. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gupta, N.; de Wispelaere, M.; Lecerf, M.; Kalia, M.; Scheel, T.; Vrati, S.; Berek, C.; Kaveri, S.V.; Desprès, P.; Lacroix-Desmazes, S.; et al. Neutralization of Japanese Encephalitis Virus by heme-induced broadly reactive human monoclonal antibody. Sci. Rep. 2015, 5, 16248. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Assunção-Miranda, I.; Cruz-Oliveira, C.; Neris, R.L.S.; Figueiredo, C.M.; Pereira, L.P.S.; Rodrigues, D.; Araujo, D.F.F.; Da Poian, A.T.; Bozza, M.T. Inactivation of Dengue and Yellow Fever viruses by heme, cobalt-protoporphyrin IX and tin-protoporphyrin IX. J. Appl. Microbiol. 2016, 120, 790–804. [Google Scholar] [CrossRef]
- Neris, R.L.S.; Figueiredo, C.M.; Higa, L.M.; Araujo, D.F.; Carvalho, C.A.M.; Verçoza, B.R.F.; Silva, M.O.L.; Carneiro, F.A.; Tanuri, A.; Gomes, A.M.O.; et al. Co-protoporphyrin IX and Sn-protoporphyrin IX inactivate Zika, Chikungunya and other arboviruses by targeting the viral envelope. Sci. Rep. 2018, 8, 9805. [Google Scholar] [CrossRef] [Green Version]
- Mendes de Oliveira, G.; Valle Garay, A.; Araújo Souza, A.; Cunha, J.; Lima, B.; Fonseca Valadares, N.; Maria, S.; Freitas, D.; Alexandre, J.; Gonçalves Barbosa, R. Structural characterization and crystallization of human TMPRSS2 protease. Biophys. J. 2018, 114, 567a. [Google Scholar] [CrossRef]
- Mousavizadeh, L.; Ghasemi, S. Genotype and phenotype of COVID-19: Their roles in pathogenesis. J. Microbiol. Immunol. Infect. 2020, 54, 159–163. [Google Scholar] [CrossRef] [PubMed]
- Walls, A.C.; Park, Y.-J.; Tortorici, M.A.; Wall, A.; McGuire, A.T.; Veesler, D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020, 181, 281–292.e6. [Google Scholar] [CrossRef] [PubMed]
- Hänel, K.; Willbold, D. SARS-CoV accessory protein 7a directly interacts with human LFA-1. Biol. Chem. 2007, 388, 1325–1332. [Google Scholar] [CrossRef]
- Zhang, C.; Zheng, W.; Huang, X.; Bell, E.W.; Zhou, X.; Zhang, Y. Protein structure and sequence reanalysis of 2019-nCoV genome refutes snakes as its intermediate host and the unique similarity between Its spike protein Insertions and HIV-1. J. Proteome Res. 2020, 19, 1351–1360. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ou, X.; Liu, Y.; Lei, X.; Li, P.; Mi, D.; Ren, L.; Guo, L.; Guo, R.; Chen, T.; Hu, J.; et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat. Commun. 2020, 11, 1620. [Google Scholar] [CrossRef] [Green Version]
- Huang, Y.; Yang, C.; Xu, X.; Xu, W.; Liu, S. Structural and functional properties of SARS-CoV-2 spike protein: Potential antivirus drug development for COVID-19. Acta Pharmacol. Sin. 2020, 41, 1141–1149. [Google Scholar] [CrossRef]
- Syllwasschy, B.F.; Beck, M.S.; Družeta, I.; Hopp, M.-T.; Ramoji, A.; Neugebauer, U.; Nozinovic, S.; Menche, D.; Willbold, D.; Ohlenschläger, O.; et al. High-affinity binding and catalytic activity of His/Tyr-based sequences: Extending heme-regulatory motifs beyond CP. Biochim. Biophys. Acta Gen. Subj. 2020, 1864, 129603. [Google Scholar] [CrossRef] [PubMed]
- Towler, P.; Staker, B.; Prasad, S.G.; Menon, S.; Tang, J.; Parsons, T.; Ryan, D.; Fisher, M.; Williams, D.; Dales, N.A.; et al. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J. Biol. Chem. 2004, 279, 17996–18007. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Heurich, A.; Hofmann-Winkler, H.; Gierer, S.; Liepold, T.; Jahn, O.; Pohlmann, S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J. Virol. 2014, 88, 1293–1307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lan, J.; Ge, J.; Yu, J.; Shan, S.; Zhou, H.; Fan, S.; Zhang, Q.; Shi, X.; Wang, Q.; Zhang, L.; et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020, 581, 215–220. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wißbrock, A.; Goradia, N.B.; Kumar, A.; Paul George, A.A.; Kühl, T.; Bellstedt, P.; Ramachandran, R.; Hoffmann, P.; Galler, K.; Popp, J.; et al. Structural insights into heme binding to IL-36α proinflammatory cytokine. Sci. Rep. 2019, 9, 16893. [Google Scholar] [CrossRef]
- Hopp, M.-T.; Alhanafi, N.; Paul George, A.A.; Hamedani, N.S.; Biswas, A.; Oldenburg, J.; Pötzsch, B.; Imhof, D. Molecular insights and functional consequences of the interaction of heme with activated protein C. Antioxid. Redox Signal. 2021, 34, 32–48. [Google Scholar] [CrossRef] [PubMed]
- Liu, W.; Li, H. COVID-19: Attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. ChemRxiv 2020. Available online: https://chemrxiv.org/articles/preprint/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173 (accessed on 6 April 2021).
- Wagener, F.A.D.T.G.; Pickkers, P.; Peterson, S.J.; Immenschuh, S.; Abraham, N.G. Targeting the heme-heme oxygenase system to prevent severe complications following COVID-19 infections. Antioxidants 2020, 9, 540. [Google Scholar] [CrossRef] [PubMed]
- Rosa, A.; Pye, V.E.; Graham, C.; Muir, L.; Seow, J.; Ng, K.W.; Cook, N.J.; Rees-Spear, C.; Parker, E.; dos Santos, M.S.; et al. SARS-CoV-2 recruits a haem metabolite to evade antibody immunity. medRxiv 2021. [Google Scholar] [CrossRef]
- Michel, C.J.; Mayer, C.; Poch, O.; Thompson, J.D. Characterization of accessory genes in coronavirus genomes. Virol. J. 2020, 17, 131. [Google Scholar] [CrossRef]
- Peherstorfer, S.; Brewitz, H.H.; Paul George, A.A.; Wißbrock, A.; Adam, J.M.; Schmitt, L.; Imhof, D. Insights into mechanism and functional consequences of heme binding to hemolysin-activating lysine acyltransferase HlyC from Escherichia coli. Biochim. Biophys. Acta Gen. Subj. 2018, 1862, 1964–1972. [Google Scholar] [CrossRef]
- Skendros, P.; Mitsios, A.; Chrysanthopoulou, A.; Mastellos, D.C.; Metallidis, S.; Rafailidis, P.; Ntinopoulou, M.; Sertaridou, E.; Tsironidou, V.; Tsigalou, C.; et al. Complement and tissue factor–enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. J. Clin. Investig. 2020, 130, 6151–6157. [Google Scholar] [CrossRef] [PubMed]
- Daniel, Y.; Hunt, B.J.; Retter, A.; Henderson, K.; Wilson, S.; Sharpe, C.C.; Shattock, M.J. Haemoglobin oxygen affinity in patients with severe COVID-19 infection. Br. J. Haematol. 2020, 190, e126–e127. [Google Scholar] [CrossRef]
- DeMartino, A.W.; Rose, J.J.; Amdahl, M.B.; Dent, M.R.; Shah, F.A.; Bain, W.; McVerry, B.J.; Kitsios, G.D.; Tejero, J.; Gladwin, M.T. No evidence of hemoglobin damage by SARS-CoV-2 infection. Haematologica 2020, 105, 2769–2773. [Google Scholar] [CrossRef]
- Belcher, J.D.; Beckman, J.D.; Balla, G.; Balla, J.; Vercellotti, G. Heme degradation and vascular injury. Antioxid. Redox Signal. 2010, 12, 233–248. [Google Scholar] [CrossRef] [Green Version]
- Bar, J.; Zosmer, A.; Hod, M.; Elder, M.G.; Sullivan, M.H. The regulation of platelet aggregation in vitro by interleukin-1beta and tumor necrosis factor-alpha: Changes in pregnancy and in pre-eclampsia. Thromb. Haemost. 1997, 78, 1255–1261. [Google Scholar] [PubMed]
- Lazarian, G.; Quinquenel, A.; Bellal, M.; Siavellis, J.; Jacquy, C.; Re, D.; Merabet, F.; Mekinian, A.; Braun, T.; Damaj, G.; et al. Autoimmune haemolytic anaemia associated with COVID-19 infection. Br. J. Haematol. 2020, 190, 29–31. [Google Scholar] [CrossRef] [PubMed]
- Capes, A.; Bailly, S.; Hantson, P.; Gerard, L.; Laterre, P.-F. COVID-19 infection associated with autoimmune hemolytic anemia. Ann. Hematol. 2020, 99, 1679–1680. [Google Scholar] [CrossRef] [PubMed]
- Conti, C.B.; Henchi, S.; Coppeta, G.P.; Testa, S.; Grassia, R. Bleeding in COVID-19 severe pneumonia: The other side of abnormal coagulation pattern? Eur. J. Intern. Med. 2020, 77, 147–149. [Google Scholar] [CrossRef] [PubMed]
- Agarwal, A.; Vishnu, V.Y.; Vibha, D.; Bhatia, R.; Gupta, A.; Das, A.; Srivastava, M.V.P. Intracerebral hemorrhage and SARS-CoV-2: Association or causation. Ann. Indian Acad. Neurol. 2020, 23, 261–264. [Google Scholar] [PubMed]
- Sahu, K.K.; Borogovac, A.; Cerny, J. COVID-19 related immune hemolysis and thrombocytopenia. J. Med. Virol. 2021, 93, 1164–1170. [Google Scholar] [CrossRef] [PubMed]
- Reiter, C.D.; Wang, X.; Tanus-Santos, J.E.; Hogg, N.; Cannon, R.O.; Schechter, A.N.; Gladwin, M.T. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat. Med. 2002, 8, 1383–1389. [Google Scholar] [CrossRef]
- Oh, J.-Y.; Hamm, J.; Xu, X.; Genschmer, K.; Zhong, M.; Lebensburger, J.; Marques, M.B.; Kerby, J.D.; Pittet, J.-F.; Gaggar, A.; et al. Absorbance and redox based approaches for measuring free heme and free hemoglobin in biological matrices. Redox. Biol. 2016, 9, 167–177. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Su, W.-L.; Lin, C.-P.; Hang, H.-C.; Wu, P.-S.; Cheng, C.-F.; Chao, Y.-C. Desaturation and heme elevation during COVID-19 infection: A potential prognostic factor of heme oxygenase-1. J. Microbiol. Immunol. Infect. 2021, 54, 113–116. [Google Scholar] [CrossRef] [PubMed]
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
Hopp, M.-T.; Domingo-Fernández, D.; Gadiya, Y.; Detzel, M.S.; Graf, R.; Schmalohr, B.F.; Kodamullil, A.T.; Imhof, D.; Hofmann-Apitius, M. Linking COVID-19 and Heme-Driven Pathophysiologies: A Combined Computational–Experimental Approach. Biomolecules 2021, 11, 644. https://doi.org/10.3390/biom11050644
Hopp M-T, Domingo-Fernández D, Gadiya Y, Detzel MS, Graf R, Schmalohr BF, Kodamullil AT, Imhof D, Hofmann-Apitius M. Linking COVID-19 and Heme-Driven Pathophysiologies: A Combined Computational–Experimental Approach. Biomolecules. 2021; 11(5):644. https://doi.org/10.3390/biom11050644
Chicago/Turabian StyleHopp, Marie-Thérèse, Daniel Domingo-Fernández, Yojana Gadiya, Milena S. Detzel, Regina Graf, Benjamin F. Schmalohr, Alpha T. Kodamullil, Diana Imhof, and Martin Hofmann-Apitius. 2021. "Linking COVID-19 and Heme-Driven Pathophysiologies: A Combined Computational–Experimental Approach" Biomolecules 11, no. 5: 644. https://doi.org/10.3390/biom11050644