Review

Pathogen Genomics and Host Cellular Susceptibility Factors of COVID-19

Fengyu Zhang, Michael D. Waters

December 14, 2020

DOI:10.36316/gcatr.02.0037

ABSTRACT

Coronavirus disease 19 (COVID-19) caused by infection with a novel severe acute respiratory syndrome virus -2 (SARS-CoV2) has evolved into a pandemic and a global public health emergency. The viral genomics, host cellular factors, and interactions are critical for establishing a viral infection and developing a related disease. This paper aims to provide an overview of viral genomics and discuss host cellular factors so far identified to be involved with the disease susceptibility. The novel pathogen is a beta coronavirus and one of seven that cause diseases to humans. It is a single strand positive-sense RNA genome virus that encodes 27 proteins, including the structural Spike protein that binds to host cell surface receptors and is a key for viral entry, and 16 nonstructural proteins play a critical role in viral replication and virulence. While the angiotensin-converting enzyme, ACE2 receptor, and the proteases TMPRSS2 and furin are established as necessary for viral entry, host factors CD147, Cathepsins, DPP4, GRP78, L-SIGN, DC-SIGN, Sialic acid, and Plasmin(ogen) may also play a role in the viral entry. The Spike protein and nonstructural proteins, and various host factors working together may contribute to the infection kinetics, high infectivity, rapid transmission, and a spectrum of clinical manifestations of COVID-19. More importantly, they can serve as potential targets in developing strategies for therapeutical prevention and intervention.

KEYWORDS

SARS-CoV-2, genomics and genetics, viral-host interaction, susceptibility, COVID-19


Copyright©2020 by Global Clinical and Translational Research.


How to cite this article:

Zhang F and Waters M. Pathogen Genomics and Host cellular Susceptibility Factors. Glob Clin Transl Res. 2020; 2 (4): 107-126. DOI:10.36316/gcatr.02.0037

REFERENCES

1.         Zhang X, Tan Y, Ling Y, Lu G, Liu F, Yi Z, et al. Viral and host factors related to the clinical outcome of COVID-19. Nature. 2020;583(7816):437-40.

2.         Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708-20.

3.         Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-3.

4.         Kim J, Chung Y, Jo H, Lee N, Kim M, Woo S, et al. Identification of Coronavirus Isolated from a Patient in Korea with COVID-19. Osong Public Health Res Perspect. 2020;11(1):3-7.

5.         Kojima A, Fujinami F, Doi K, Yasoshima A, Okaniwa A. Isolation and properties of sialodacryoadenitis virus of rats. Jikken Dobutsu. 1980;29(4):409-18.

6.         Vijgen L, Keyaerts E, Lemey P, Maes P, Van Reeth K, Nauwynck H, et al. Evolutionary history of the closely related group 2 coronaviruses: porcine hemagglutinating encephalomyelitis virus, bovine coronavirus, and human coronavirus OC43. J Virol. 2006;80(14):7270-4.

7.         Stout AE, Andre NM, Jaimes JA, Millet JK, Whittaker GR. Coronaviruses in cats and other companion animals: Where does SARS-CoV-2/COVID-19 fit? Vet Microbiol. 2020; 247: 108777.

8.         Zhang Q, Zhang H, Huang K, Yang Y, Hui X, Gao J, et al. SARS-CoV-2 neutralizing serum antibodies in cats: a serological investigation. BioRxiv. 2020;doi: https://doi.org/10.1101/2020.04.01.021196.

9.         Fung TS, Liu DX. Human Coronavirus: Host-Pathogen Interaction. Annu Rev Microbiol. 2019;73:529-57.

10.      Fan Y, Zhao K, Shi Z-L, Zhou P. Bat coronaviruses in China. Viruses. 2019;11(3):210.

11.      Woo PC, Lau SK, Lam CS, Lau CC, Tsang AK, Lau JH, et al. Discovery of seven novel Mammalian and avian corona-viruses in the genus deltacoronavirus supports bat corona-viruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus. J Virol. 2012;86(7):3995-4008.

12.      Hamre D, Kindig DA, Mann J. Growth and intracellular development of a new respiratory virus. J Virol. 1967;1(4):810-6.

13.      Tyrrell DA, Bynoe ML. Cultivation of a Novel Type of Common-Cold Virus in Organ Cultures. Br Med J. 1965;1(5448):1467-70.

14.      McIntosh K, Kapikian AZ, Turner HC, Hartley JW, Parrott RH, Chanock RM. Seroepidemiologic studies of coronavirus infection in adults and children. Am J Epidemiol. 1970;91(6):585-92.

15.      Cavallaro JJ, Monto AS. Community-wide outbreak of infection with a 229E-like coronavirus in Tecumseh, Michigan. J Infect Dis. 1970;122(4):272-9.

16.      Li W, Shi Z, Yu M, Ren W, Smith C, Epstein JH, et al. Bats are natural reservoirs of SARS-like coronaviruses. Science. 2005;310(5748):676-9.

17.      van der Hoek L, Pyrc K, Jebbink MF, Vermeulen-Oost W, Berkhout RJ, Wolthers KC, et al. Identification of a new human coronavirus. Nat Med. 2004;10(4):368-73.

18.      Arden KE, Nissen MD, Sloots TP, Mackay IM. New human coronavirus, HCoV-NL63, associated with severe lower respiratory tract disease in Australia. J Med Virol. 2005;75(3):455-62.

19.      Woo PC, Lau SK, Chu CM, Chan KH, Tsoi HW, Huang Y, et al. Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia. J Virol. 2005;79(2):884-95.

20.      de Groot RJ, Baker SC, Baric RS, Brown CS, Drosten C, Enjuanes L, et al. Middle East respiratory syndrome corona-virus (MERS-CoV): announcement of the Coronavirus Study Group. J Virol. 2013;87(14):7790-2.

21.      Desforges M, Le Coupanec A, Stodola JK, Meessen-Pinard M, Talbot PJ. Human coronaviruses: viral and cellular factors involved in neuroinvasiveness and neuropathogenesis. Virus Res. 2014;194:145-58.

22.      Yeager CL, Ashmun RA, Williams RK, Cardellichio CB, Shapiro LH, Look AT, et al. Human aminopeptidase N is a receptor for human coronavirus 229E. Nature. 1992;357 (6377):420-2.

23.      Cui T, Theuns S, Xie J, Van den Broeck W, Nauwynck HJ. Role of Porcine Aminopeptidase N and Sialic Acids in Porcine Coronavirus Infections in Primary Porcine Enterocytes. Viruses. 2020;12(4).

24.      Parks JM, Smith  JC. How to discover antiviral drugs quickly. New Eng J Med. 2020;382(23):2261-4.

25.      da Silva SJR, Alves da Silva CT, Mendes RPG, Pena L. Role of nonstructural proteins in the pathogenesis of SARS-CoV-2. J Med Virol. 2020;92(9):1427-9.

26.      Uddin M, Mustafa F, Rizvi TA, Loney T, Suwaidi HA, Al-Marzouqi AHH, et al. SARS-CoV-2/COVID-19: Viral Genomics, Epidemiology, Vaccines, and Therapeutic Interventions. Viruses. 2020;12(5).

27.      Kim D, Lee JY, Yang JS, Kim JW, Kim VN, Chang H. The Architecture of SARS-CoV-2 Transcriptome. Cell. 2020; 181(4):914-21.e10.

28.      Robson F, Khan KS, Le TK, Paris C, Demirbag S, Barfuss P, et al. Coronavirus RNA Proofreading: Molecular Basis and Therapeutic Targeting. Molecular Cell. 2020;79(5):710-27.

29.      Snijder EJ, Decroly E, Ziebuhr J. The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing. Adv Virus Res. 2016;96:59-126.

30.      Shin D, Mukherjee R, Grewe D, Bojkova D, Baek K, Bhattacharya A, et al. Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature. 2020;587(7835):657-62.

31.      Jin Y, Yang H, Ji W, Wu W, Chen S, Zhang W, et al. Virology, Epidemiology, Pathogenesis, and Control of COVID-19. Viruses. 2020;12(4).

32.      Lei X, Dong X, Ma R, Wang W, Xiao X, Tian Z, et al. Activation and evasion of type I interferon responses by SARS-CoV-2. Nat Commun. 2020;11(1):3810.

33.      Thoms M, Buschauer R, Ameismeier M, Koepke L, Denk T, Hirschenberger M, et al. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science. 2020;369(6508):1249-55.

34.      Angeletti S, Benvenuto D, Bianchi M, Giovanetti M, Pascarella S, Ciccozzi M. COVID-2019: The role of the nsp2 and nsp3 in its pathogenesis. J Med Virol. 2020;92(6):584-8.

35.      Baez-Santos YM, St John SE, Mesecar AD. The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antiviral Res. 2015;115:21-38.

36.      Frieman M, Yount B, Agnihothram S, Page C, Donaldson E, Roberts A, et al. Molecular determinants of severe acute respiratory syndrome coronavirus pathogenesis and virulence in young and aged mouse models of human disease. J Virol. 2012;86(2):884-97.

37.      Littler DR, Gully BS, Colson RN, Rossjohn J. Crystal Structure of the SARS-CoV-2 Non-structural Protein 9, Nsp9. iScience. 2020;23(7):101258.

38.      Tai W, He L, Zhang X, Pu J, Voronin D, Jiang S, et al. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol. 2020;17(6):613-20.

39.      Regla-Nava JA, Nieto-Torres JL, Jimenez-Guardeño JM, Fernandez-Delgado R, Fett C, Castaño-Rodríguez C, et al. Severe acute respiratory syndrome coronaviruses with mutations in the E protein are attenuated and promising vaccine candidates. J Virol. 2015;89(7):3870-87.

40.      DeDiego ML, Nieto-Torres JL, Jiménez-Guardeño JM, Regla-Nava JA, Alvarez E, Oliveros JC, et al. Severe acute respiratory syndrome coronavirus envelope protein regulates cell stress response and apoptosis. PLoS Pathog. 2011;7(10): e1002315.

41.      Jimenez-Guardeño JM, Nieto-Torres JL, DeDiego ML, Regla-Nava JA, Fernandez-Delgado R, Castaño-Rodriguez C, et al. The PDZ-binding motif of severe acute respiratory syndrome coronavirus envelope protein is a determinant of viral pathogenesis. PLoS Pathog. 2014;10(8):e1004320.

42.      Burbelo PD, Riedo FX, Morishima C, Rawlings S, Smith D, Das S, et al. Detection of Nucleocapsid Antibody to SARS-CoV-2 is More Sensitive than Antibody to Spike Protein in COVID-19 Patients. medRxiv. 2020;doi:

https://doi.org/10.1101/2020.04.20.20071423.

43.      Li JY, Liao CH, Wang Q, Tan YJ, Luo R, Qiu Y, et al. The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway. Virus Res. 2020;286:198074.

44.      Srinivasan S, Cui H, Gao Z, Liu M, Lu S, Mkandawire W, et al. Structural Genomics of SARS-CoV-2 Indicates Evolutionary Conserved Functional Regions of Viral Proteins. Viruses. 2020;12(4).

45.      Diaz J. SARS-CoV-2 Molecular Network Structure. Front Physiol. 2020;11:870.

46.      Michel CJ, Mayer C, Poch O, Thompson JD. Characterization of accessory genes in coronavirus genomes. Virol J. 2020;17(1):131.

47.      Castano-Rodriguez C, Honrubia JM, Gutierrez-Alvarez J, DeDiego ML, Nieto-Torres JL, Jimenez-Guardeno JM, et al. Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis. mBio. 2018;9(3).

48.      Siu KL, Yuen KS, Castaño-Rodriguez C, Ye ZW, Yeung ML, Fung SY, et al. Severe acute respiratory syndrome corona-virus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitina-tion of ASC. Faseb j. 2019;33(8):8865-77.

49.      Issa E, Merhi G, Panossian B, Salloum T, Tokajian S. SARS-CoV-2 and ORF3a: Nonsynonymous Mutations, Functional Domains, and Viral Pathogenesis. mSystems. 2020;5(3).

50.      Holland LA, Kaelin EA, Maqsood R, Estifanos B, Wu LI, Varsani A, et al. An 81-Nucleotide Deletion in SARS-CoV-2 ORF7a Identified from Sentinel Surveillance in Arizona (January to March 2020). J Virol. 2020;94(14).

51.      Kopecky-Bromberg SA, Martinez-Sobrido L, Palese P. 7a protein of severe acute respiratory syndrome coronavirus inhibits cellular protein synthesis and activates p38 mitogen-activated protein kinase. J Virol. 2006;80(2):785-93.

52.      Báez-Santos YM, St John SE, Mesecar AD. The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antiviral Res. 2015;115:21-38.

53.      Zhao J, Sun J, He W, Ji X, Gao Q, Zhai X, et al. Snapshot of the evolution and mutation patterns of SARS-CoV-2. bioRxiv. 2020;doi:10.1101/2020.07.04.187435:2020.07.04.187435.

54.      Jauregui AR, Savalia D, Lowry VK, Farrell CM, Wathelet MG. Identification of residues of SARS-CoV nsp1 that differentially affect inhibition of gene expression and antiviral signaling. PloS one. 2013;8(4):e62416.

55.      Benedetti F, Snyder GA, Giovanetti M, Angeletti S, Gallo RC, Ciccozzi M, et al. Emerging of a SARS-CoV-2 viral strain with a deletion in nsp1. J Transl Med. 2020;18(1):329.

56.      Benvenuto D, Angeletti S, Giovanetti M, Bianchi M, Pascarella S, Cauda R, et al. Evolutionary analysis of SARS-CoV-2: how mutation of Non-Structural Protein 6 (NSP6) could affect viral autophagy. J Infect. 2020;81(1):e24-e7.

57.      Cornillez-Ty CT, Liao L, Yates JR, 3rd, Kuhn P, Buchmeier MJ. Severe acute respiratory syndrome coronavirus nonstructural protein 2 interacts with a host protein complex involved in mitochondrial biogenesis and intracellular signaling. J Virol. 2009;83(19):10314-8.

58.      Davies JP, Almasy KM, McDonald EF, Plate L. Comparative multiplexed interactomics of SARS-CoV-2 and homologous coronavirus non-structural proteins identifies unique and shared host-cell dependencies. bioRxiv. 2020;doi: https://doi.org/10.1101/2020.07.13.201517.

59.      Stobart CC, Sexton NR, Munjal H, Lu X, Molland KL, Tomar S, et al. Chimeric exchange of coronavirus nsp5 proteases (3CLpro) identifies common and divergent regulatory determinants of protease activity. J Virol. 2013;87(23):12611-8.

60.      Angelini MM, Akhlaghpour M, Neuman BW, Buchmeier MJ. Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles. mBio. 2013;4(4).

61.      Cottam EM, Whelband MC, Wileman T. Coronavirus NSP6 restricts autophagosome expansion. Autophagy. 2014;10 (8):1426-41.

62.      Kirchdoerfer RN, Ward AB. Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nat Commun. 2019;10(1):2342.

63.      Rogstam A, Nyblom M, Christensen S, Sele C, Talibov VO, Lindvall T, et al. Crystal Structure of Non-Structural Protein 10 from Severe Acute Respiratory Syndrome Coronavirus-2. Int J Mol Sci. 2020;21(19).

64.      Hillen HS, Kokic G, Farnung L, Dienemann C, Tegunov D, Cramer P. Structure of replicating SARS-CoV-2 polymerase. Nature. 2020.

65.      Jiang Y, Yin W, Xu HE. RNA-dependent RNA polymerase: Structure, mechanism, and drug discovery for COVID-19. Biochem Biophys Res Commun. 2020.

66.      Gao Y, Yan L, Huang Y, Liu F, Zhao Y, Cao L, et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science. 2020;368(6492):779-82.

67.      Jang KJ, Jeong S, Kang DY, Sp N, Yang YM, Kim DE. A high ATP concentration enhances the cooperative translocation of the SARS coronavirus helicase nsP13 in the unwinding of duplex RNA. Sci Rep. 2020;10(1):4481.

68.      Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583(7816):459-68.

69.      Deng X, Hackbart M, Mettelman RC, O'Brien A, Mielech AM, Yi G, et al. Coronavirus nonstructural protein 15 mediates evasion of dsRNA sensors and limits apoptosis in macrophages. Proc Natl Acad Sci U S A. 2017;114(21):E4251-E60.

70.      Lin S, Chen H, Ye F, Chen Z, Yang F, Zheng Y, et al. Crystal structure of SARS-CoV-2 nsp10/nsp16 2'-O-methylase and its implication on antiviral drug design. Signal Transduct Target Ther. 2020;5(1):131.

71.      Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-80 e8.

72.      Siu KL, Yuen KS, Castano-Rodriguez C, Ye ZW, Yeung ML, Fung SY, et al. Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. FASEB J. 2019;33(8):8865-77.

73.      73.    Ren Y, Shu T, Wu D, Mu J, Wang C, Huang M, et al. The ORF3a protein of SARS-CoV-2 induces apoptosis in cells. Cellular & molecular immunology. 2020;17(8):881-3.

74.      Konno Y, Kimura I, Uriu K, Fukushi M, Irie T, Koyanagi Y, et al. SARS-CoV-2 ORF3b Is a Potent Interferon Antagonist Whose Activity Is Increased by a Naturally Occurring Elongation Variant. Cell Rep. 2020;32(12):108185.

75.      Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virol J. 2019;16(1):69.

76.      Thomas S. The Structure of the Membrane Protein of SARS-CoV-2 Resembles the Sugar Transporter SemiSWEET. Pathog Immun. 2020;5(1):342-63.

77.      Taylor JK, Coleman CM, Postel S, Sisk JM, Bernbaum JG, Venkataraman T, et al. Severe Acute Respiratory Syndrome Coronavirus ORF7a Inhibits Bone Marrow Stromal Antigen 2 Virion Tethering through a Novel Mechanism of Glycosylation Interference. J Virol. 2015;89(23):11820-33.

78.      Pfefferle S, Krähling V, Ditt V, Grywna K, Mühlberger E, Drosten C. Reverse genetic characterization of the natural genomic deletion in SARS-Coronavirus strain Frankfurt-1 open reading frame 7b reveals an attenuating function of the 7b protein in-vitro and in-vivo. Virol J. 2009;6:131.

79.      Sung SC, Chao CY, Jeng KS, Yang JY, Lai MM. The 8ab protein of SARS-CoV is a luminal ER membrane-associated protein and induces the activation of ATF6. Virology. 2009; 387(2): 402-13.

80.      Mu J, Xu J, Zhang L, Shu T, Wu D, Huang M, et al. SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells. Sci China Life Sci. 2020;63(9):1-4.

81.      Shi CS, Qi HY, Boularan C, Huang NN, Abu-Asab M, Shelhamer JH, et al. SARS-coronavirus open reading frame-9b supp-resses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome. J Immunol. 2014; 193(6):3080-9.

82.      Dominguez Andres A, Feng Y, Campos AR, Yin J, Yang CC, James B, et al. SARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in Cells. bioRxiv. 2020;doi:

83.      https://doi.org/10.1101/2020.08.18.256776.

84.      Thunders M, Delahunt B. Gene of the month: TMPRSS2 (transmembrane serine protease 2). J Clin Pathol. 2020; 73(12):773-6.

85.      Walls A, Park Y, Tortorici M, Wall A, McGuire A, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020;181(2):281-92.

86.      Pillay TS. Gene of the month: the 2019-nCoV/SARS-CoV-2 novel coronavirus spike protein. J Clin Pathol. 2020; 73(7): 366-9.

87.      Bestle D, Heindl MR, Limburg H, Van Lam van T, Pilgram O, Moulton H, et al. TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells. Life Sci Alliance. 2020;3(9):e202000786.

88.      Nao N, Yamagishi J, Miyamoto H, Igarashi M, Manzoor R, Ohnuma A, et al. Genetic Predisposition To Acquire a Polybasic Cleavage Site for Highly Pathogenic Avian Influenza Virus Hemagglutinin. mBio. 2017;8(1):e02298-16.

89.      Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2. Nat Med. 2020;26(4):450-2.

90.      Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367 (6483): 1260-3.

91.      Lu J, Sun PD. High affinity binding of SARS-CoV-2 spike protein enhances ACE2 carboxypeptidase activity. bioRxiv. 2020;doi: https://doi.org/10.1101/2020.07.01.182659.

92.      Joshi S, Joshi M, Degani M. Tackling SARS-CoV-2: proposed targets and repurposed drugs. Future Medicinal Chemistry.12(17):1579-601.

93.      White MA, Lin W, Cheng X. Discovery of COVID-19 Inhibitors Targeting the SARS-CoV-2 Nsp13 Helicase. J Phys Chem Lett. 2020;11(21):9144-51.

94.      Wong HH, Kumar P, Tay FP, Moreau D, Liu DX, Bard F. Genome-Wide Screen Reveals Valosin-Containing Protein Requirement for Coronavirus Exit from Endosomes. J Virol. 2015;89(21):11116-28.

95.      Soh WT, Liu Y, Nakayama EE, Ono C, Torii S, Nakagami H, et al. The N-terminal domain of spike glycoprotein mediates SARS-CoV-2 infection by associating with L-SIGN and DC-SIGN. bioRxiv.2020;doi:https://doi.org/10.1101/2020.11.05.369264:2020.11.05.369264.

96.      Huang IC, Bosch BJ, Li F, Li W, Lee KH, Ghiran S, et al. SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells. J Biol Chem. 2006;281(6):3198-203.

97.      Wang K, Chen W, Zhou Y-S, Lian J-Q, Zhang Z, Du P, et al. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. bioRxiv. 2020; doi:

https://doi.org/10.1101/2020.03.14.988345.

98.      Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020;581(7807):221-4.

99.      Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA, Dijkman R, et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature. 2013;495(7440):251-4.

100.  Hulswit RJG, Lang Y, Bakkers MJG, Li W, Li Z, Schouten A, et al. Human coronaviruses OC43 and HKU1 bind to 9-O-acetylated sialic acids via a conserved receptor-binding site in spike protein domain A. Proceedings of the National Academy of Sciences. 2019;116(7):2681-90.

101.  Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res. 2020;176:104742.

102.  Ibrahim IM, Abdelmalek DH, Elshahat ME, Elfiky AA. COVID-19 spike-host cell receptor GRP78 binding site prediction. J Infect. 2020;80(5):554-62.

103.  Zhao X, Zheng S, Chen D, Zheng M, Li X, Li G, et al. LY6E Restricts the Entry of Human Coronaviruses, Including the Currently Pandemic SARS-CoV-2. J Virol. 2020.

104.  Milanetti E, Miotto M, Di Rienzo L, Monti M, Gosti G, Ruocco G. In-Silico evidence for two receptors based strategy of SARS-CoV-2. 2020;24(https://arxiv.org/abs/2003.11107).

105.  Renteria AE, Endam Mfuna L, Adam D, Filali-Mouhim A, Maniakas A, Rousseau S, et al. Azithromycin Downregulates Gene Expression of IL-1beta and Pathways Involving TMPRSS2 and TMPRSS11D Required by SARS-CoV-2. Am J Respir Cell Mol Biol. 2020.

106.  Paulpandi M, Kavithaa K, Asaikkutty A, Balachandar V, Ayyadurai N, Arul N. Could host cell receptor alteration prevent SARS-CoV-2 viral entry? - Hype or hope. Eur Rev Med Pharmacol Sci. 2020;24(8):4554-7.

107.  Turner AJ. Chapter 25 - ACE2 Cell Biology, Regulation, and Physiological Functions. In: Unger T, Steckelings UM, dos Santos RAS, editors. The Protective Arm of the Renin Angiotensin System (RAS). Boston: Academic Press; 2015. p. 185-9.

108.  Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.

109.  Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450-4.

110.  Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science. 2005;309(5742):1864-8.

111.  Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J Virol. 2020;94(7).

112.  Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 2020;12(1):8.

113.  Ali F, Elserafy M, Alkordi MH, Amin M. ACE2 coding variants in different populations and their potential impact on SARS-CoV-2 binding affinity. Biochem Biophys Rep. 2020:100798.

114.  Ferrario C, Jessup J, Chappell M, Averill D, Brosnihan K, Tallant E, et al. Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2. Circulation. 2005;111(20):2605-10.

115.  Diaz JH. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. Journal of Travel Medicine. 2020;27(3).

116.  Hippisley-Cox J, Young D, Coupland C, Channon KM, Tan PS, Harrison DA, et al. Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people. Heart. 2020;106:1503-11.

117.  de Abajo FJ, Rodriguez-Martin S, Lerma V, Mejia-Abril G, Aguilar M, Garcia-Luque A, et al. Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet. 2020;395(10238):1705-14.

118.  Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875-9.

119.  Hikmet F, Méar L, Edvinsson Å, Micke P, Uhlén M, Lindskog C. The protein expression profile of ACE2 in human tissues. Molecular Systems Biology. 2020;16(7):e9610.

120.  Chappel MC, Ferrario CM. ACE and ACE2: their role to balance the expression of angiotensin II and angiotensin-(1-7). Kidney Int. 2006;70(1):8-10.

121.  Gaddam RR, Chambers S, Bhatia M. ACE and ACE2 in inflammation: a tale of two enzymes. Inflamm Allergy Drug Targets. 2014;13(4):224-34.

122.  121. Santos RAS, Oudit GY, Verano-Braga T, Canta G, Steckelings UM, Bader M. The renin-angiotensin system: going beyond the classical paradigms. Am J Physiol Heart Circ Physiol. 2019;316(5):H958-h70.

123.  Ocaranza MP, Godoy I, Jalil JE, Varas M, Collantes P, Pinto M, et al. Enalapril attenuates downregulation of Angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension. 2006;48(4):572-8.

124.  Nataraj C, Oliverio MI, Mannon RB, Mannon PJ, Audoly LP, Amuchastegui CS, et al. Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. The Journal of clinical investigation. 1999;104(12):1693-701.

125.  Pagliaro P, Penna C. ACE/ACE2 Ratio: A Key Also in 2019 Coronavirus Disease (Covid-19)? Front Med (Lausanne). 2020;7:335.

126.  Qiu X, Tian Y, Jiang X, Xu J, Zhang Q, Huang J. Clinical Characteristics of Coronavirus Disease 19. Glob Clin Transl Res. 2020;2(3):85-99.

127.  Wu Z, Hu R, Zhang C, Ren W, Yu A, Zhou X. Elevation of plasma angiotensin II level is a potential pathogenesis for the critically ill COVID-19 patients. Critical Care. 2020;24(1):290.

128.  Chung MK, Karnik S, Saef J, Bergmann C, Barnard J, Lederman MM, et al. SARS-CoV-2 and ACE2: The biology and clinical data settling the ARB and ACEI controversy. EBioMedicine. 2020;58:102907.

129.  Achua JK, Chu KY, Ibrahim E, Khodamoradi K, Delma KS, Iakymenko OA, et al. Histopathology and Ultrastructural Findings of Fatal COVID-19 Infections on Testis. World J Mens Health. 2020.

130.  Bradley BT, Maioli H, Johnston R, Chaudhry I, Fink SL, Xu H, et al. Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series. Lancet. 2020;396(10247):320-32.

131.  Sonzogni A, Previtali G, Seghezzi M, Grazia Alessio M, Gianatti A, Licini L, et al. Liver histopathology in severe COVID 19 respiratory failure is suggestive of vascular alterations. Liver Int. 2020;40(9):2110-6.

132.  Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120-8.

133.  Chaipan C, Kobasa D, Bertram S, Glowacka I, Steffen I, Tsegaye TS, et al. Proteolytic activation of the 1918 influenza virus hemagglutinin. Journal of virology. 2009;83(7):3200-11.

134.  Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N. TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection. J Virol. 2019;93(6).

135.  Zhang F, Hughes C. Clinical epidemiology of coronavirus disease 2019: defined on current research. Glob Clin Transl Res. 2020;2(3):54-72.

136.  Stopsack KH, Mucci LA, Antonarakis ES, Nelson PS, Kantoff PW. TMPRSS2 and COVID-19: Serendipity or Opportunity for Intervention? Cancer Discov. 2020;10(6):779-82.

137.  Strope JD, Pharm DC, Figg WD. TMPRSS2: Potential Biomarker for COVID-19 Outcomes. J Clin Pharmacol. 2020;60(7):801-7.

138.  Renteria AE, Mfuna Endam L, Adam D, Filali-Mouhim A, Maniakas A, Rousseau S, et al. Azithromycin Downregulates Gene Expression of IL-1beta and Pathways Involving TMPRSS2 and TMPRSS11D Required by SARS-CoV-2. Am J Respir Cell Mol Biol. 2020;63(5):707-9.

139.  Hoffmann M, Kleine-Weber H, Pohlmann S. A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells. Mol Cell. 2020;78(4):779-84 e5.

140.  Lukassen S, Chua RL, Trefzer T, Kahn NC, Schneider MA, Muley T, et al. SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J. 2020;39(10):e105114.

141.  Drak Alsibai K. Expression of angiotensin-converting enzyme 2 and proteases in COVID-19 patients: A potential role of cellular FURIN in the pathogenesis of SARS-CoV-2. Med Hypotheses. 2020;143:109893.

142.  Mentlein R. Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory peptides. Regul Pept. 1999;85(1):9-24.

143.  Chen X. Biochemical properties of recombinant prolyl dipeptidases DPP-IV and DPP8. Adv Exp Med Biol. 2006;575:27-32.

144.  Kolb AF, Maile J, Heister A, Siddell SG. Characterization of functional domains in the human coronavirus HCV 229E receptor. J Gen Virol. 1996;77 ( Pt 10):2515-21.

145.  Kolb AF, Hegyi A, Siddell SG. Identification of residues critical for the human coronavirus 229E receptor function of human aminopeptidase N. J Gen Virol. 1997;78 ( Pt 11):2795-802.

146.  Bassendine MF, Bridge SH, McCaughan GW, Gorrell MD. Covid-19 and co-morbidities: a role for Dipeptidyl Peptidase 4 (DPP4) in disease severity? J Diabetes. 2020.

147.  Vankadari N, Wilce JA. Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg Microbes Infect. 2020;9(1):601-4.

148.  Morimoto C, Schlossman SF. The structure and function of CD26 in the T-cell immune response. Immunological Reviews. 1998;161(1):55-70.

149.  Barchetta I, Cavallo MG, Baroni MG. COVID-19 and diabetes: Is this association driven by the DPP4 receptor? Potential clinical and therapeutic implications. Diabetes Res Clin Pract. 2020;163:108165.

150.  Strollo R, Pozzilli P. DPP4 inhibition: Preventing SARS-CoV-2 infection and/or progression of COVID-19? Diabetes Metab Res Rev. 2020:e3330.

151.  Wang K, Chen W, Zhou Y-S, Lian J-Q, Zhang Z, Du P, et al. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. bioRxiv. 2020:2020.03.14.988345.

152.  Crosnier C, Bustamante LY, Bartholdson SJ, Bei AK, Theron M, Uchikawa M, et al. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature. 2011;480(7378):534-7.

153.  Ulrich H, Pillat MM. CD147 as a Target for COVID-19 Treatment: Suggested Effects of Azithromycin and Stem Cell Engagement. Stem Cell Rev Rep. 2020;16(3):434-40.

154.  Bian H, Zheng Z-H, Wei D, Zhang Z, Kang W-Z, Hao C-Q, et al. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial. medRxiv. 2020;doi: https://doi.org/10.1101/2020.03.21.20040691.

155.  Chen Z, Mi L, Xu J, Yu J, Wang X, Jiang J, et al. Function of HAb18G/CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus. J Infect Dis. 2005;191(5):755-60.

156.  Rosas IO, Richards TJ, Konishi K, Zhang Y, Gibson K, Lokshin AE, et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008;5(4):e93.

157.  George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. The Lancet Respiratory Medicine. 2020;8(8):807-15.

158.  Radzikowska U, Ding M, Tan G, Zhakparov D, Peng Y, Wawrzyniak P, et al. Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hyper-tension, and COVID-19 risk factors. Allergy. 2020;75 (11): 2829-45.

159.  Ibrahim IM, Abdelmalek DH, Elfiky AA. GRP78: A cell's response to stress. Life Sci. 2019;226:156-63.

160.  Palmeira A, Sousa E, Koseler A, Sabirli R, Goren T, Turkcuer I, et al. Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection. Pharmaceuticals (Basel). 2020;13(6):132.

161.  Sudeep HV, Gouthamchandra K, Shyamprasad K. Molecular docking analysis of Withaferin A from Withania somnifera with the Glucose regulated protein 78 (GRP78) receptor and the SARS-CoV-2 main protease. Bioinformation. 2020;16(5):411-7.

162.  Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, 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(1):1620.

163.  Daniloski Z, Jordan TX, Wessels H-H, Hoagland DA, Kasela S, Legut M, et al. Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells. Cell.

164.  Yu J, Liu SL. Emerging Role of LY6E in Virus-Host Interactions. Viruses. 2019;11(11):1020;https://doi.org/10.3390/v11111020.

165.  Zhao X, Li J, Winkler CA, An P, Guo JT. IFITM Genes, Variants, and Their Roles in the Control and Pathogenesis of Viral Infections. Front Microbiol. 2018;9:3228.

166.  Chen D, Hou Z, Jiang D, Zheng M, Li G, Zhang Y, et al. GILT restricts the cellular entry mediated by the envelope glycoproteins of SARS-CoV, Ebola virus and Lassa fever virus. Emerg Microbes Infect. 2019;8(1):1511-23.

167.  Liu SY, Aliyari R, Chikere K, Li G, Marsden MD, Smith JK, et al. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity. 2013;38(1):92-105.

168.  Shu Q, Lennemann NJ, Sarkar SN, Sadovsky Y, Coyne CB. ADAP2 Is an Interferon Stimulated Gene That Restricts RNA Virus Entry. PLoS Pathog. 2015;11(9):e1005150.

169.  Yu J, Liu SL. Emerging Role of LY6E in Virus-Host Interactions. Viruses. 2019;11(11).

170.  Ille AM, Kishel E, Bodea R, Ille A, Lamont H, Amico-Ruvio S. Protein LY6E as a candidate for mediating transport of adeno-associated virus across the human blood-brain barrier. J Neurovirol. 2020;26:769–78.

171.  Luo L, McGarvey P, Madhavan S, Kumar R, Gusev Y, Upadhyay G. Distinct lymphocyte antigens 6 (Ly6) family members Ly6D, Ly6E, Ly6K and Ly6H drive tumorigenesis and clinical outcome. Oncotarget. 2016;7(10):11165-93.

172.  Gardner JP, Durso RJ, Arrigale RR, Donovan GP, Maddon PJ, Dragic T, et al. L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus. Proceedings of the National Academy of Sciences. 2003;100(8):4498-503.

173.  Olofsson S, Kumlin U, Dimock K, Arnberg N. Avian influenza and sialic acid receptors: more than meets the eye? Lancet Infect Dis. 2005;5(3):184-8.

174.  Li W, Hulswit RJG, Widjaja I, Raj VS, McBride R, Peng W, et al. Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein. Proc Natl Acad Sci U S A. 2017;114(40):E8508-e17.

175.  Fantini J, Di Scala C, Chahinian H, Yahi N. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents. 2020; 55(5):105960.

176.  Wielgat P, Rogowski K, Godlewska K, Car H. Coronaviruses: Is Sialic Acid a Gate to the Eye of Cytokine Storm? From the Entry to the Effects. Cells. 2020;9(9):1963; https://doi.org/10.3390/cells9091963.

177.  Engin AB, Engin ED, Engin A. Dual function of sialic acid in gastrointestinal SARS-CoV-2 infection. Environ Toxicol Pharmacol. 2020;79:103436.

178.  Seth S, Batra J, Srinivasan S. COVID-19: Targeting Proteases in Viral Invasion and Host Immune Response. Front Mol Biosci. 2020;7:215.

179.  Ji HL, Zhao R, Matalon S, Matthay MA. Elevated Plasmin-(ogen) as a Common Risk Factor for COVID-19 Susceptibility. Physiol Rev. 2020;100(3):1065-75.

180.  Kaur U, Chakrabarti SS, Ojha B, Pathak BK, Singh A, Saso L, et al. Targeting host cell proteases to prevent SARS-CoV-2 invasion. Curr Drug Targets. 2020, https://doi.org/10.2174/1389450121666200924113243.

181.  Umemura Y, Yamakawa K, Kiguchi T, Nishida T, Kawada M, Fujimi S. Hematological Phenotype of COVID-19-Induced Coagulopathy: Far from Typical Sepsis-Induced Coagulopathy. J Clin Med. 2020;9(9):2875; https://doi.org/10.3390/jcm9092875.

182.  Huang Y, Lyu X, Li D, Wang L, Wang Y, Zou W, et al. A cohort study of 676 patients indicates D-dimer is a critical risk factor for the mortality of COVID-19. PLoS One. 2020;15(11):e0242045.

183.  Solun B, Shoenfeld Y. Inhibition of metalloproteinases in therapy for severe lung injury due to COVID-19. Med Drug Discov. 2020;7:100052.

184.  Thierry AR. Anti-protease Treatments Targeting Plasmin(ogen) and Neutrophil Elastase May Be Beneficial in Fighting COVID-19. Physiol Rev. 2020;100(4):1597-8.

185.  Heissig B, Salama Y, Takahashi S, Osada T, Hattori K. The multifaceted role of plasminogen in inflammation. Cell Signal. 2020;75:109761.