SARS-CoV-2: Review of Structure, Genome, Genetic Variants, and Vaccines

Document Type : Review Article

Authors

Department of Biology, Faculty of Sciences, Arak University, Arak, Iran

Abstract

The emergence and outbreak of the deadly novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, become a global health problem in the last two years. SARS-CoV-2 is an enveloped virus with a non-segmented single-strand positive-sense RNA. It has some similarities with other coronaviruses, especially the SARS-CoV. However, the specific features of this virus have changed its pathogenicity and transmissibility compared to other coronaviruses. The distinctive structural differences of the SARS-CoV-2 spike protein have a key role in the kinetics of viral load and a broad range of virus tissue tropism. Because of these differences, SARS-CoV-2 has a greater affinity for binding host cell receptor angiotensin-converting enzyme 2 than SARS-CoV. Since its emergence, the SARS-CoV-2 genome has undergone several mutations. However, a small number can alter the virus antigenicity and clinical features of the disease, leading to the formation of different SARS-CoV-2 variants. Some of these variants have higher transmissibility, severity, and impact on host immunity than the original SARS-CoV-2. Although there are currently no specific therapeutic interventions for coronavirus disease 2019 (COVID-19), manufacturers are working to make and update vaccines by continuously monitoring antigenic and genetic changes in the SARS-CoV-2 population worldwide. Some of these vaccines are very effective against different variants of the virus, therefore in some countries, with widespread vaccination and compliance with health protocols, people have largely returned to normal living conditions. To better understand SARS-CoV-2, in this article, we reviewed its classification, genome organization, structure, and life cycle. In addition, an overview of the mutations occurring in the spike protein and the characteristics of the different variants is given here. Finally, vaccines produced against this coronavirus were briefly introduced.

Keywords


Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R. 2003. Coronavirus main proteinase (3CLpro) Structure: basis for design of anti-SARS drugs. Sci 300(5626): 1763-1767.
Anand P, Stahel VP. 2021. Review the safety of Covid-19 mRNA vaccines: a review. Patient Saf 15(1): 20. doi: 10.1186/s13037-021-00291-9.
Aoe T. 2020. Pathological aspects of COVID-19 as a conformational disease and the use of pharmacological chaperones as a potential therapeutic strategy. Front Pharmacol 11: 1095. doi: 10.3389/fphar.2020.01095.
Araki K, Gangappa S, Dillehay DL, Rouse BT, Larsen CP, Ahmed R. 2010. Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation. Exp Med 207(11): 2355-2367.
Bernal JL, Andrews N, Gower C, Gallagher E, Simmons R, Thelwall S, Ramsay M. 2021. Effectiveness of COVID-19 vaccines against the B.1.617.2 variant. N Engl J Med https://doi.org/10.1101/2021.05.22.21257658.
Bojkova D, Klann K, Koch B, Widera M, Krause D, Ciesek S, Münch C. 2020. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature 583(7816): 469-472.
Brown CG, Nixon KS, Senanayake SD, Nixon KS, Brian DA. 2007. An RNA stem-loop within the bovine coronavirus nsp1 coding region is a cis-acting element in defective interfering RNA replication. J Virol 81(14): 7716-7724.
Chan JFW, Kok KH, Zhu Z, Chu H, To KKW, Yuan S, Yuen KY. 2020. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect 9(1): 221-236.
Chen Y, Cai H, Pan J, Xiang N, Tien P, Ahola T, Guo D. 2009. Functional screen reveals SARS coronavirus nonstructural protein nsp14 as a novel cap N7 methyltransferase. Proc Natl Acad Sci 106(9): 3484-3489.
Collier DA, De Marco A, Ferreira IATM, Meng B, Datir RP, Walls AC, Gupta RK. 2021. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. Nature 593(7857): 136-141.
Davies NG, Abbott S, Barnard RC, Jarvis CI, Kucharski AJ, Munday JD, Edmunds WJ. 2021a. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science 372(6538): eabg3055. doi: 10.1126/science.abg3055
Davies NG, Jarvis CI, Edmunds WJ, Jewell NP, Diaz-Ordaz K, Keogh RH, Pearson CAB. 2021b. Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7. Nature 593(7858): 270-274.
de Haan CA, de Wit M, Kuo L, Montalto-Morrison C, Haagmans BL, Weiss SR, Rottier PJ. 2003. The glycosylation status of the murine hepatitis coronavirus M protein affects the interferogenic capacity of the virus in vitro and its ability to replicate in the liver but not the brain. Virology 312(2): 395-406.
Deng X, Hackbart M, Mettelman RC, O’Brien A, Mielech AM, Yi G, Baker SC. 2017. Coronavirus nonstructural protein 15 mediates evasion of dsRNA sensors and limits apoptosis in macrophages. Proc Natl Acad Sci 114(21): 4251-4260.
Fallah A, Razavi Nikoo H, Abbasi H, Mohammad-Hasani A, Hosseinzadeh Colagar A, Khosravi A. 2021. The features of pathobiology and clinical translation of approved treatments for coronavirus disease 2019 (COVID-19). Intervirology (In press): https://doi.org/10.1159/000520234.
Fehr AR, Perlman S. 2015. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol 1282: 1-23.
Funk T, Pharris A, Spiteri G, Bundle N, Melidou A, Carr M, Adlhoch C. 2021. Characteristics of SARS-CoV-2 variants of concern B.1.1.7, B.1.351 or P.1. data from seven EU/EEA countries, weeks 38/2020 to 10/2021 Eurosurveillance 26(16): 2100348.
Ge XY, Li JL, Yang XL, Chmura AA, Zhu G, Epstein JH, Shi ZL. 2013. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature 503(7477): 535-538.
Graham RL, Sims AC, Brockway SM, Baric RS, Denison MR. 2005. The nsp2 replicase proteins of murine hepatitis virus and severe acute respiratory syndrome coronavirus are dispensable for viral replication. J Virol 79(21): 13399-13411.
Greaney AJ, Loes AN, Crawford KHD, Starr TN, Malone KD, Chu HY, Bloom JD. 2021. Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies. Cell Host Microbe 29(3): 463-476.
Harvey WT, Carabelli AM, Jackson B, Gupta RK, Thomson EC, Harrison EM, Robertson DL. 2021. SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol 19(7): 409-424.
Hoffmann M, Hofmann-Winkler H, Krüger N, Kempf A, Nehlmeier I, Graichen L, Pöhlmann S. 2021. SARS-CoV-2 variant B.1.617 is resistant to Bamlanivimab and evades antibodies induced by infection and vaccinatio. Cell Rep 109415. https://doi.org/10.1016/j.celrep.2021.109415.
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Pöhlmann S. 2020. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181(2): 271-280.
Huang C, Lokugamage KG, Rozovics JM, Narayanan K, Semler BL, Makino S. 2011. Alphacoronavirus transmissible gastroenteritis virus nsp1 protein suppresses protein translation in mammalian cells and in cell-free HeLa cell extracts but not in rabbit reticulocyte lysate. J Virol 85(1): 638-643.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Cao B. 2020. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395(10223): 497-506.
Ivanov KA, Thiel V, Dobbe JC, Van Der Meer Y, Snijder EJ, Ziebuhr J. 2004a. Multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase. J Virol 78(11): 5619-5632.
Ivanov KA, Ziebuhr J. 2004b. Human coronavirus 229E nonstructural protein 13: characterization of duplex-unwinding, nucleoside triphosphatase, and RNA 5′-triphosphatase activities. J Virol 78(14): 7833-7838.
Jacobs L, van der Zeijst BA, Horzinek MC. 1986. Characterization and translation of transmissible gastroenteritis virus mRNAs. J Virol 57(3):1010-1015.
Jangra S, Ye C, Rathnasinghe R, Stadlbauer D; Personalized Virology Initiative study group, Krammer F, Simon V. 2021. SARS-CoV-2 spike E484K mutation reduces antibody neutralisation. Lancet Microbe 2(7): e283-e284.
Jiang HW, Zhang HN, Meng QF, Xie J, Li Y, Chen H, Tao SC. 2020. SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70. Cell Mol Immunol 17(9): 998-1000.
Kemp SA, Collier DA, Datir RP, Ferreira IATM, Gayed S, Jahun A, Gupta RK. 2021. SARS-CoV-2 evolution during treatment of chronic infection. Nature 592(7853): 277-282.
Kimura I, Kosugi Y, Wu J, Yamasoba D, Butlertanaka PE, Tanaka LY, Sato K. 2021. SARS-CoV-2 Lambda variant exhibits higher infectivity and immune resistance. BioRxiv [Preprint]. 07.28.454085. https://doi.org/10.1101/2021.07.28.454085.
Krafcikova P, Silhan J, Nencka R, Boura E. 2020. Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin. Nat Commun 11(1): 3717. doi:10.1038/s41467-020-17495-9.
Lei J, Kusov Y, Hilgenfeld R. 2018. Nsp3 of coronaviruses: structures and functions of a large multi-domain protein. Antivir Res 149: 58-74.
Liu Q, Johnson RF, Leibowitz JL. 2001. Secondary structural elements within the 3′ untranslated region of mouse hepatitis virus strain JHM genomic RNA. J Virol 75(24): 12105-12113.
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Tan W. 2020. Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 395(10224): 565-574.
Lukassen S, Chua RL, Trefzer T, Kahn NC, Schneider MA, Muley T, Eils R. 2020. SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J 39(10): e105114. doi: 10.15252/embj.20105114.
McCallum M, Bassi J, De Marco A, Chen A, Walls AC, Di Iulio J, Veesler D. 2021. SARS-CoV-2 immune evasion by variant B.1.427/B.1.429. BioRxiv [Preprint]. https://doi.org/10.1101/2021.03.31.437925.
Miknis ZJ, Donaldson EF, Umland TC, Rimmer RA, Baric RS, Schultz LW. 2009. Severe acute respiratory syndrome coronavirus nsp9 dimerization is essential for efficient viral growth. J Virol 83(7): 3007-3018.
Minor PD. 2015. Live attenuated vaccines: Historical successes and current challenges. Virology 479: 379-392.
Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E. 2020. A Novel Coronavirus Emerging in China - Key Questions for Impact Assessment. N Engl J Med 382(8): 692-694.
Nelson CA, Pekosz A, Lee CA, Diamond MS, Fremont DH. 2005. Structure and intracellular targeting of the SARS-coronavirus Orf7a accessory protein. Structure 13(1): 75-85.
Nelson CW, Ardern Z, Goldberg TL, Meng C, Kuo CH, Ludwig C, Wei X. 2020. Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic. Elife 9: e59633. doi: 10.7554/eLife.59633.
Oostra M, Hagemeijer MC, van Gent M, Bekker CP, Te Lintelo EG, Rottier PJ, de Haan CA. 2008. Topology and membrane anchoring of the coronavirus replication complex: not all hydrophobic domains of nsp3 and nsp6 are membrane spanning. J Virol 82(24): 12392-12405.
Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IFN, Poon LL, HKU/UCH SARS study group. 2003. clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study. Lancet 361: 1767-1772.
Perlman S, Netland J. 2009. Coronaviruses post-SARS: update on replication and pathogenesis. Nat Rev Microbiol 7(6): 439-450.
Public Health England. SARS-CoV-2 variants of concern and variants under investigation in England Technical briefing 17 2021 [Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/997418/Variants_of_Concern_VOC_Technical_Briefing_17.pdf]
Qiu Y, Xu K. 2020. Functional studies of the coronavirus nonstructural proteins. STEMed 1(2): e39. doi: 10.37175/stemedicine.v1i2.39.
Ren Y, Shu T, Wu D, Mu J, Wang C, Huang M, Zhou X. 2020. The orf3a protein of sars-cov-2 induces apoptosis in cells. Cell Mol Immunol 17(8): 881-883.
Sakai Y, Kawachi K, Terada Y, Omori H, Matsuura Y, Kamitani W. 2017. Two-amino acids change in the nsp4 of SARS coronavirus abolishes viral replication. Virology 510: 165-174.
Schaecher SR, Mackenzie JM, Pekosz A. 2007. The ORF7b protein of severe acute respiratory syndrome coronavirus (SARS-CoV) is expressed in virus-infected cells and incorporated into SARS-CoV particles. J Virol 81(2): 718-731.
Schoeman D, Fielding BC. 2019. Coronavirus envelope protein: Current knowledge. Virol J 16(1): 1-22.
Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A, Li F. 2020b. Cell entry mechanisms of sars-cov-2. Proc Natl Acad Sci 117(21): 11727-11734.
Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, Li F. 2020a. Structural basis of receptor recognition by sars-cov-2. Nature 581(7807): 221-224.
Sharma K, Koirala A, Nicolopoulos K, Chiu C, Wood N, Britton PN. 2021, Vaccines for covid-19: where do we stand in 2021? Paediatr Respir Rev Mini-symposium: COVID 19: The second year. https://doi.org/10.1016/j.prrv.2021.07.00.
Shi J, Wen Z, Zhong G, Yang H, Wang C, Huang B, Bu Z. 2020. Susceptibility of ferrets, cats, dogs, and other domesticated animals to sars-coronavirus 2. Science 368(6494): 1016-1020.
Snijder EJ, Bredenbeek PJ, Dobbe JC, Thiel V, Ziebuhr J, Poon LL, Gorbalenya AE. 2003. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J Mol Biol 331(5): 991-1004.
Song W, Gui M, Wang X, Xiang Y. 2018. Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog 14(8): e1007236. doi: 10.1371/journal.ppat.1007236.
Song Z, Xu Y, Bao L, Zhang L, Yu P, Qu Y, Qin C. 2019. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses 11(1): 59. doi: 10.3390/v11010059.
Starr TN, Greaney AJ, Hilton SK, Ellis D, Crawford KHD, Dingens AS, Bloom JD. 2020. Deep Mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding. Cell 182(5): 1295-1310.
Su S, Wong G, Shi W, Liu J, Lai ACK, Zhou J, Gao GF. 2016. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 24(6): 490-502.
Subissi L, Posthuma CC, Collet A, Zevenhoven-Dobbe JC, Gorbalenya AE, Decroly E, Imbert I. 2014. One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities. Proc Natl Acad Sci 111(37): 3900-3909.
Tan HX, Juno JA, Lee WS, Barber-Axthelm I, Kelly HG, Wragg KM, Wheatley AK. 2021. Immunogenicity of prime-boost protein subunit vaccine strategies against SARS-CoV-2 in mice and macaques. Nat Commun 12: 1-10.
Tok TT, Tatar G. 2017. Structures and functions of coronavirus proteins: molecular modeling of viral nucleoprotein. Int. J Virol Infect Dis 2(1): 001-007.
V’Kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. 2021. Coronavirus biology and replication: Implications for SARS-CoV-2. Nat Rev Microbiol 19(3): 155-170.
Vrba SM, Kirk NM, Brisse ME, Liang Y, Ly H. 2020. Development and applications of viral vectored vaccines to combat zoonotic and emerging public health threats. Vaccines 8(4): 680. doi: 10.3390/vaccines8040680.
Walker PJ, Siddell SG, Lefkowitz EJ, Mushegian AR, Dempsey DM, Dutilh BE, Davison AJ. 2019. Changes to virus taxonomy and the international code of virus classification and nomenclature ratified by the group of viruses (2019). Arch Virol 164(9): 2417-2429.
Wan Y, Shang J, Graham R, Baric RS, Li F. 2020. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol 94(7): e00127-20.
Wang P, Nair MS, Liu L, Iketani S, Luo Y, Guo Y, Ho DD. 2021. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 593(7857):130-135.
Wibmer CK, Ayres F, Hermanus T, Madzivhandila M, Kgagudi P, Oosthuysen B, Moore PL. 2021. SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. Nat Med 27(4):622-625.
Wise J. 2021. Covid-19: the E484K mutation and the risks it poses. BMJ 372: n359.
Woo PC, Lau SK, Lam CS, Lau CC, Tsang AK, Lau JH, Yuen KY. 2012. Discovery of seven novel Mammalian and avian coronaviruses in the genus Deltacoronavirus supports bat coronaviruses as the gene source of Alphacoronavirus and Betacoronavirus and avian coronaviruses as the gene source of Gammacoronavirus and Deltacoronavirus. J Virol 86(7): 3995- 4008.
Word Health Organization. 2021. COVID-19 weekly epidemiological update edition 55, published 31 August 2021 [Available from: https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---31-august-2021].
Yoshimoto FK. 2020. The Proteins of Severe Acute respiratory syndrome coronavirus-2 (SARS CoV-2 or n-COV19), the cause of COVID-19. Protein J 39(3): 198-216.
Zhai Y, Sun F, Li X, Pang H, Xu X, Bartlam M, Rao Z. 2005. Insights into SARS-CoV transcription and replication from the structure of the nsp7-nsp8 hexadecamer. Nat Struct Mol Biol 12(11): 980- 986.
Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Hilgenfeld R. 2020b. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors. Science 368(6489): 409- 412.
Zhang T, Wu Q, Zhang Z. 2020a. Probable pangolin origin of SARS-CoV-2 associated with the COVID-19 outbreak. Curr Biol 30(7): 1346-1351.
Zhang, Y, Zhang J, Chen Y, Luo B, Yuan Y, Huang F, Zhang H. 2020c. The ORF8 protein of SARS-CoV-2 mediates immune evasion through potently downregulating MHC-I. Proc Natl Acad Sci 118(23): e2024202118.
Zhao J, Falcon A, Zhou H, Netlan J, Enjuanes L, Brena PP, Perlman S. 2009. Severe acute respiratory syndrome coronavirus protein 6 is required for optimal replication. J Virol 83(5): 2368-2373.
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Shi ZL. 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579 (7798): 270-273.
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Tan W. 2020. A novel coronavirus from patients with pneumonia in China, 2019. NEJM 382(8): 727- 733.
Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, Wu J. 2020. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 382(12): 1177-1179.
Zust R, Cervantes-Barragan L, Habjan M, Maier R, Neuman BW, Ziebuhr J, Thiel V. 2011. Ribose 2สน-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat Immunol 12(2): 137-143.