Understanding the Molecular Mechanism(s) of SARS-CoV2 Infection and Propagation in Human to Discover Potential Preventive and Therapeutic Approach

Author(s): Sibi Raj, Vaishali Chandel, Brijesh Rathi, Dhruv Kumar*

Journal Name: Coronaviruses
The World's First International Journal Dedicated to Coronaviruses

Volume 1 , Issue 1 , 2020

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Exported across the world might create a serious controversy. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection into the host undergoes a huge number of complex replicative machineries which remains unclear. Understanding the mechanism (s) of replication and mode of infection of SARS-CoV2 to human cells will help us in the development of novel vaccines or drugs for the eradication and prevention of the disease. This review compiles the knowledge of SARS-CoV2 replicative machinery, mode of infection to the human cells and the development of drugs and vaccines which are currently under clinical trials.

Keywords: Coronavirus, COVID-19, SARS, ACE-2, spike protein, vaccines, infection.

Corman VM, Landt O, Kaiser M, et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill 2020; 25(3): 3.
[http://dx.doi.org/10.2807/1560-7917.ES.2020.25.3.2000045] [PMID: 31992387]
Banerjee A, Kulcsar K, Misra V, Frieman M, Mossman K. Bats and Coronaviruses. Viruses 2019; 11(1): 41.
[http://dx.doi.org/10.3390/v11010041] [PMID: 30634396]
Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol 2020; 92(4): 418-23.
[http://dx.doi.org/10.1002/jmv.25681] [PMID: 31967327]
Zhou P, Yang X-L, Wang X-G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270-3.
[http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID: 32015507]
Chan JFW, Kok KH, Zhu Z, et al. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect 2020; 9(1): 221-36.
[http://dx.doi.org/10.1080/22221751.2020.1719902] [PMID: 31987001]
Yan R, Zhang Y, Guo Y, Xia L, Zhou Q. Structural basis for the recognition of the 2019-nCoV by human ACE2. bioRxiv 2020.
Newton AH, Cardani A, Braciale TJ. The host immune response in respiratory virus infection: balancing virus clearance and immunopathology. Semin Immunopathol 2016; 38(4): 471-82.
[http://dx.doi.org/10.1007/s00281-016-0558-0] [PMID: 26965109]
Han Y, Du J, Su H, et al. Identification of diverse bat alphacoronaviruses and betacoronaviruses in china provides new insights into the evolution and origin of coronavirus-related diseases. Front Microbiol 2019; 10: 1900.
[http://dx.doi.org/10.3389/fmicb.2019.01900] [PMID: 31474969]
Chan JFW, Yuan S, Kok KH, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020; 395(10223): 514-23.
[http://dx.doi.org/10.1016/S0140-6736(20)30154-9] [PMID: 31986261]
Chen T, Rui J, Wang Q, Zhao Z, Cui J-A, Yin L. A mathematical model for simulating the transmission of Wuhan novel Coronavirus. bioRxiv 2020.
Chu CM, Cheng VCC, Hung IFN, et al. HKU/UCH SARS Study Group. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004; 59(3): 252-6.
[http://dx.doi.org/10.1136/thorax.2003.012658] [PMID: 14985565]
Mesenchymal Stem Cell Treatment for Pneumonia Patients Infected With 2019 Novel Coronavirus Case Med Res 2020.
McBride R, van Zyl M, Fielding BC. The coronavirus nucleocapsid is a multifunctional protein. Viruses 2014; 6(8): 2991-3018.
[http://dx.doi.org/10.3390/v6082991] [PMID: 25105276]
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; 176104742
[http://dx.doi.org/10.1016/j.antiviral.2020.104742] [PMID: 32057769]
Klausegger A, Strobl B, Regl G, Kaser A, Luytjes W, Vlasak R. Identification of a coronavirus hemagglutinin-esterase with a substrate specificity different from those of influenza C virus and bovine coronavirus. J Virol 1999; 73(5): 3737-43.
[http://dx.doi.org/10.1128/JVI.73.5.3737-3743.1999] [PMID: 10196267]
Bárcena M, Oostergetel GT, Bartelink W, et al. Cryo-electron tomography of mouse hepatitis virus: Insights into the structure of the coronavirion. Proc Natl Acad Sci USA 2009; 106(2): 582-7.
[http://dx.doi.org/10.1073/pnas.0805270106] [PMID: 19124777]
Mortola E, Roy P. Efficient assembly and release of SARS coronavirus-like particles by a heterologous expression system. FEBS Lett 2004; 576(1-2): 174-8.
[http://dx.doi.org/10.1016/j.febslet.2004.09.009] [PMID: 15474033]
Deng X, StJohn SE, Osswald HL, et al. Coronaviruses resistant to a 3C-like protease inhibitor are attenuated for replication and pathogenesis, revealing a low genetic barrier but high fitness cost of resistance. J Virol 2014; 88(20): 11886-98.
[http://dx.doi.org/10.1128/JVI.01528-14] [PMID: 25100843]
Götte B, Liu L, McInerney GM. The enigmatic alphavirus non-structural protein 3 (nsP3) revealing its secrets at last. Viruses 2018; 10(3): 105.
[http://dx.doi.org/10.3390/v10030105] [PMID: 29495654]
Kirchdoerfer RN, Ward AB. Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nat Commun 2019; 10(1): 2342.
[http://dx.doi.org/10.1038/s41467-019-10280-3] [PMID: 31138817]
Tan YJ, Goh PY, Fielding BC, et al. Profiles of antibody responses against severe acute respiratory syndrome coronavirus recombinant proteins and their potential use as diagnostic markers. Clin Diagn Lab Immunol 2004; 11(2): 362-71.
[http://dx.doi.org/10.1128/CDLI.11.2.362-371.2004] [PMID: 15013989]
Liu C, Xu HY, Liu DX. Induction of caspase-dependent apoptosis in cultured cells by the avian coronavirus infectious bronchitis virus. J Virol 2001; 75(14): 6402-9.
[http://dx.doi.org/10.1128/JVI.75.14.6402-6409.2001] [PMID: 11413307]
Lavi E, Wang Q, Weiss SR, Gonatas NK. Syncytia formation induced by coronavirus infection is associated with fragmentation and rearrangement of the Golgi apparatus. Virology 1996; 221(2): 325-34.
[http://dx.doi.org/10.1006/viro.1996.0382] [PMID: 8661443]
Antonio GE, Wong KT, Hui DSC, et al. Thin-section CT in patients with severe acute respiratory syndrome following hospital discharge: preliminary experience. Radiology 2003; 228(3): 810-5.
[http://dx.doi.org/10.1148/radiol.2283030726] [PMID: 12805557]
Ning Q, Liu M, Kongkham P, et al. The nucleocapsid protein of murine hepatitis virus type 3 induces transcription of the novel fgl2 prothrombinase gene. J Biol Chem 1999; 274(15): 9930-6.
[http://dx.doi.org/10.1074/jbc.274.15.9930] [PMID: 10187767]
Marten NW, Stohlman SA, Bergmann CC. MHV infection of the CNS: mechanisms of immune-mediated control. Viral Immunol 2001; 14(1): 1-18.
[http://dx.doi.org/10.1089/08828240151061329] [PMID: 11270593]
Weiss RC, Scott FW. Antibody-mediated enhancement of disease in feline infectious peritonitis: comparisons with dengue hemorrhagic fever. Comp Immunol Microbiol Infect Dis 1981; 4(2): 175-89.
[http://dx.doi.org/10.1016/0147-9571(81)90003-5] [PMID: 6754243]
Leparc-Goffart I, Hingley ST, Chua MM, Phillips J, Lavi E, Weiss SR. Targeted recombination within the spike gene of murine coronavirus mouse hepatitis virus-A59: Q159 is a determinant of hepatotropism. J Virol 1998; 72(12): 9628-36.
[http://dx.doi.org/10.1128/JVI.72.12.9628-9636.1998] [PMID: 9811696]
Mou H, Raj VS, van Kuppeveld FJM, Rottier PJM, Haagmans BL, Bosch BJ. The receptor binding domain of the new Middle East respiratory syndrome coronavirus maps to a 231-residue region in the spike protein that efficiently elicits neutralizing antibodies. J Virol 2013; 87(16): 9379-83.
[http://dx.doi.org/10.1128/JVI.01277-13] [PMID: 23785207]
Guan Y, Zheng BJ, He YQ, et al. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science 2003; 302(5643): 276-8.
[http://dx.doi.org/10.1126/science.1087139] [PMID: 12958366]
Belouzard S, Chu VC, Whittaker GR. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc Natl Acad Sci USA 2009; 106(14): 5871-6.
[http://dx.doi.org/10.1073/pnas.0809524106] [PMID: 19321428]
Bosch BJ, van der Zee R, de Haan CAM, Rottier PJM. The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. J Virol 2003; 77(16): 8801-11.
[http://dx.doi.org/10.1128/JVI.77.16.8801-8811.2003] [PMID: 12885899]
Baranov PV, Henderson CM, Anderson CB, Gesteland RF, Atkins JF, Howard MT. Programmed ribosomal frameshifting in decoding the SARS-CoV genome. Virology 2005; 332(2): 498-510.
[http://dx.doi.org/10.1016/j.virol.2004.11.038] [PMID: 15680415]
Brierley I, Digard P, Inglis SC. Characterization of an efficient coronavirus ribosomal frameshifting signal: requirement for an RNA pseudoknot. Cell 1989; 57(4): 537-47.
[http://dx.doi.org/10.1016/0092-8674(89)90124-4] [PMID: 2720781]
Ziebuhr J, Snijder EJ, Gorbalenya AE. Virus-encoded proteinases and proteolytic processing in the Nidovirales. J Gen Virol 2000; 81(Pt 4): 853-79.
[http://dx.doi.org/10.1099/0022-1317-81-4-853] [PMID: 10725411]
Snijder EJ, Bredenbeek PJ, Dobbe JC, et al. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J Mol Biol 2003; 331(5): 991-1004.
[http://dx.doi.org/10.1016/S0022-2836(03)00865-9] [PMID: 12927536]
Sethna PB, Hofmann MA, Brian DA. Minus-strand copies of replicating coronavirus mRNAs contain antileaders. J Virol 1991; 65(1): 320-5.
[http://dx.doi.org/10.1128/JVI.65.1.320-325.1991] [PMID: 1985203]
Brown CG, Nixon KS, Senanayake SD, Brian DA. An RNA stem-loop within the bovine coronavirus nsp1 coding region is a cis-acting element in defective interfering RNA replication. J Virol 2007; 81(14): 7716-24.
[http://dx.doi.org/10.1128/JVI.00549-07] [PMID: 17475638]
Raman S, Brian DA. Stem-loop IV in the 5′ untranslated region is a cis-acting element in bovine coronavirus defective interfering RNA replication. J Virol 2005; 79(19): 12434-46.
[http://dx.doi.org/10.1128/JVI.79.19.12434-12446.2005] [PMID: 16160171]
Liu Q, Johnson RF, Leibowitz JL. Secondary structural elements within the 3′ untranslated region of mouse hepatitis virus strain JHM genomic RNA. J Virol 2001; 75(24): 12105-13.
[http://dx.doi.org/10.1128/JVI.75.24.12105-12113.2001] [PMID: 11711601]
Bentley K, Keep SM, Armesto M, Britton P. Identification of a noncanonically transcribed subgenomic mRNA of infectious bronchitis virus and other gammacoronaviruses. J Virol 2013; 87(4): 2128-36.
[http://dx.doi.org/10.1128/JVI.02967-12] [PMID: 23221558]
Krijnse-Locker J, Ericsson M, Rottier PJM, Griffiths G. Characterization of the budding compartment of mouse hepatitis virus: evidence that transport from the RER to the Golgi complex requires only one vesicular transport step. J Cell Biol 1994; 124(1-2): 55-70.
[http://dx.doi.org/10.1083/jcb.124.1.55] [PMID: 8294506]
de Haan CAM, Rottier PJM. Molecular interactions in the assembly of coronaviruses. Adv Virus Res 2005; 64: 165-230.
[http://dx.doi.org/10.1016/S0065-3527(05)64006-7] [PMID: 16139595]
Bos ECW, Luytjes W, Van Der Meulen H, Koerten HK, Spaan WJM. The production of recombinant infectious DI-particles of a murine coronavirus in the absence of helper virus. Virology 1996; 218: 52-60.
Siu YL, Teoh KT, Lo J, et al. The M, E, and N structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles. J Virol 2008; 82(22): 11318-30.
[http://dx.doi.org/10.1128/JVI.01052-08] [PMID: 18753196]
Fischer F, Stegen CF, Masters PS, Samsonoff WA. Analysis of constructed E gene mutants of mouse hepatitis virus confirms a pivotal role for E protein in coronavirus assembly. J Virol 1998; 72(10): 7885-94.
[http://dx.doi.org/10.1128/JVI.72.10.7885-7894.1998] [PMID: 9733825]
Haijema BJ, Volders H, Rottier PJM. Live, attenuated coronavirus vaccines through the directed deletion of group-specific genes provide protection against feline infectious peritonitis. J Virol 2004; 78(8): 3863-71.
[http://dx.doi.org/10.1128/JVI.78.8.3863-3871.2004] [PMID: 15047802]
Bande F, Arshad SS, Bejo MH, Moeini H, Omar AR. Progress and challenges toward the development of vaccines against avian infectious bronchitis. J Immunol Res 2015; 2015424860
[http://dx.doi.org/10.1155/2015/424860] [PMID: 25954763]
Spruth M, Kistner O, Savidis-Dacho H, et al. A double-inactivated whole virus candidate SARS coronavirus vaccine stimulates neutralising and protective antibody responses. Vaccine 2006; 24(5): 652-61.
[http://dx.doi.org/10.1016/j.vaccine.2005.08.055] [PMID: 16214268]
Eroglu E, Singh A, Bawage S, et al. Immunogenicity of RSV F DNA Vaccine in BALB/c Mice. Adv Virol 2016; 20167971847
[http://dx.doi.org/10.1155/2016/7971847] [PMID: 27688769]
Sui J, Li W, Murakami A, et al. Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc Natl Acad Sci USA 2004; 101(8): 2536-41.
[http://dx.doi.org/10.1073/pnas.0307140101] [PMID: 14983044]
Roldão A, Mellado MCM, Castilho LR, Carrondo MJT, Alves PM. Virus-like particles in vaccine development. Expert Rev Vaccines 2010; 9(10): 1149-76.
[http://dx.doi.org/10.1586/erv.10.115] [PMID: 20923267]
Mifsud EJ, Hayden FG, Hurt AC. Antivirals targeting the polymerase complex of influenza viruses. Antiviral Res 2019; 169104545
[http://dx.doi.org/10.1016/j.antiviral.2019.104545] [PMID: 31247246]
Britton P, Armesto M, Cavanagh D, Keep S. Modification of the avian coronavirus infectious bronchitis virus for vaccine development. Bioeng Bugs 2012; 3(2): 114-9.
[PMID: 22179147]
Leronlimab (PRO 140) Combined With Carboplatin in Patients With CCR5+ mTNBC Case Med Res 2000.
NIH Clinical Trial of Investigational Vaccine for COVID-19 Begins. 2020.
Clover Successfully Produced 2019-nCoV Subunit Vaccine Candidate and Detected Cross- Reacting Antibodies from Sera of Multiple Infected Patients 2020.

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Year: 2020
Page: [73 - 81]
Pages: 9
DOI: 10.2174/2666796701999200617155013

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