SARS-CoV-2
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [[1]]; Associate Editor(s)-in-Chief: Syed Ali Rizvi M.B;B.S
Overview
The Coronavirus disease-2019 (COVID-19), is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 forms a distinct lineage with bat SARS-like coronaviruses . The virus is closely related (96.3%) to bat coronavirus RaTG13, based on phylogenetic analysis, that belong to the order Nidovirales, family Coronaviridae, genus Betacoronavirus, and subgenus Sarbecovirus [1]. Coronaviruses are enveloped, single-stranded RNA viruses that can infect a wide range of hosts including avian, wild, domestic mammalian species, and humans. Coronaviruses are well known for their ability to mutate rapidly, alter tissue tropism, cross the species barrier, and adapt to different epidemiological situations.[2] Six human coronaviruses have been reported since the 1960s; OC43, 229E, NL63, HKU1, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). First case of COVID-19 was reported in Wuhan, Hubei province, China, in December 2019, associated with the Huanan Seafood Wholesale Market. On March 11, 2020 the Novel Coronavirus Disease, COVID-19, was declared a pandemic by the World Health Organization
Taxonomy
- SARS-CoV-2 belong to the order nidovirale, family coronaviridae.
- Coronaviridae is classified into two subfamilies.
- Torovirinae
- Coronavirinae
- Coronavirinae is further classified on the basis of phylogenetic analysis and genome structure into four genera:
- Alpha coronavirus (αCoV).
- Beta coronavirus (βCoV).
- Gamma coronavirus (γCoV).
- Delta coronavirus (δCoV), which contain 17, 12, 2, and 7 unique species, respectively (ICTV 2018).
- CoV-2 falls under beta coronavirus.
Biology
Structure
- Coronaviruses are enveloped, icosahedral symmetric particles, approximately 80–220 nm in diameter containing a non-segmented, single-strand, positive-sense RNA genome of about 26–32 kb in size. [3]
- Corona in Latin means crown, and this name was attributed to the virus due to the presence of spike projections from the virus envelope that give it the shape of a crown under the electron microscope.
- Nido means nest and refers to the ability of the viruses of this order to make a nested set of subgenomic mRNA
| Stuructural Protein | Function of protein |
|---|---|
| Spike (S) Protein | Critical for binding to host cell receptor (ACE-2 receptor) and facilitate entry to host cell.[5][6] |
| Envelope (E) Protein | Envelope (E) protein is a small, integral membrane protein involved in several aspects of the virus’ life cycle, such as assembly,
budding, envelope formation, and pathogenesis.[7] |
| Membrane (M) Protein | Membrane (M) protein is a component of the viral envelope that plays a central role in virus
morphogenesis and assembly via its interactions with other viral proteins[8] |
| Nucleocapsid (N) Protein | Nucleocapsid (N) protein is to package the viral RNA genome within the viral envelope into a ribonucleoprotein (RNP)
complex called the capsid.[9] |
Structural Proteins
- Spike (S) Protein
- Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases.
- Early studies indicate that SARS-CoV-2 uses the SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2) for entry and transmembrane protease serine 2 (TMPRSS2) for S protein priming.[10][11]
- The spike (S) glycoprotein is a type I transmembrane glycoprotein that plays an important role in mediating viral infection.
- The S proteins consist of two subunits, S1 and S2.
- The S1 subunit binds the cellular receptor through its receptor-binding domain (RBD), followed by conformational changes in the S2 subunit, which allows the fusion peptide to insert into the host target cell membrane.[12]
- Envelope (E) Protein
- The CoV envelope (E) protein is a small, integral membrane protein involved in several aspects of the virus’ life cycle, such as assembly, budding, envelope formation, and pathogenesis.[13]
- Recent studies have expanded on its structural motifs and topology, its functions as an ion-channelling viroporin, and its interactions with both other CoV proteins and host cell proteins.[14]
- Recombinant CoVs lacking E exhibit significantly reduced viral titres, crippled viral maturation, or yield propagation incompetent progeny, demonstrating the importance of E in virus production and maturation.[15]
- Membrane (M) Protein
- The CoV membrane (M) protein is a component of the viral envelope that plays a central role in virus morphogenesis and assembly via its interactions with other viral proteins.
- M is located among the S proteins in the virus envelope along with small amounts of E and is the primary driver of the virus budding process.
- During assembly of the authentic virion M interacts with itself, with the nucleocapsid protein N, with E and with the S protein.
- The M protein has dominant cellular immunogenicity and elicits a strong humoral response which suggests it could serve as a potential target in vaccine design.[16] [17]
- Nucleocapsid (N) Protein[18]
- The primary function of the nucleocapsid (N) protein is to package the viral RNA genome within the viral envelope into a ribonucleoprotein (RNP) complex called the capsid.
- Ribonucleocapsid packaging is a fundamental part of viral self-assembly and replication.
- Additionally, the N-protein of the SARS-CoV-2 affects host cell responses and may serve regulatory roles during its viral life cycle.
Corona Virus Life Cycle:
Attachment and Entry:
- The attachment of the virion to the host cell is associated with the interactions between the S protein and its receptor.
- The sites of receptor binding domains (RBD) within the S1 region of a coronavirus (SARS-CoV-2) S protein is at the C Terminus.[19]
- SARS-CoV use angiotensin-converting enzyme 2 (ACE2) as their receptor[20]
- After binding to the receptor, the virus next step is to gain access to the host cell cytosol.
- This is generally done by cathepsin,TMPRRS2 or some other protease. This is followed by fusion of the viral and cellular membranes.
- S protein cleavage occurs at two sites within the S2 portion of the protein, with the first cleavage important for separating the RBD (Receptor binding domain) and fusion domains of the S protein [21] and the second for exposing the fusion peptide (cleavage at S2′).
- Fusion occurs within acidified endosomes.
- Cleavage at S2′ exposes a fusion peptide that inserts into the membrane, which is followed by joining of two heptad repeats in S2 forming an antiparallel six-helix bundle[22].The formation of this bundle allows for the mixing of viral and cellular membranes, resulting in fusion and ultimately release of the viral genome into the cytoplasm.
RNA Replicase Protein Expression:
- The next step in the coronavirus lifecycle is translation and assembly of the viral replicase complexes from the virion genomic RNA.
Replication and Transcription:
- The translation and assembly of the viral replicase complexes is followed by viral RNA synthesis.
- Viral RNA synthesis produces both genomic and sub-genomic RNAs.
- Sub-genomic RNAs serve as mRNAs for the structural and accessory genes which reside downstream of the replicase polyproteins. All positive-sense sub-genomic RNAs are 3′ co-terminal with the full-length viral genome and thus form a set of nested RNAs, a distinctive property of the order Nidovirales. Both genomic and sub-genomic RNAs are produced through negative-strand intermediates. These negative-strand intermediates are only about 1 % as abundant as their positive-sense counterparts and contain both poly-uridylate and anti-leader sequences.[23]
Tropism
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preferentially infects cells in the respiratory tract, which is lung alveolar epithelial cell .[24][25]
- SARS-CoV-2 can be detected in multiple organs, including the lungs, heart, liver, brain, pharynx and kidneys.[26]
- In a study, it shows that highest levels of SARS-CoV-2 copies per cell were detected in the respiratory tract, and lower levels were detected the kidneys, liver, heart, brain, and blood. These findings indicate a broad organotropism of SARS-CoV-2.[27]
Natural Reservoir
References
- ↑ Zhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang; Hu, Ben; Zhang, Lei; Zhang, Wei; Si, Hao-Rui; Zhu, Yan; Li, Bei; Huang, Chao-Lin; Chen, Hui-Dong; Chen, Jing; Luo, Yun; Guo, Hua; Jiang, Ren-Di; Liu, Mei-Qin; Chen, Ying; Shen, Xu-Rui; Wang, Xi; Zheng, Xiao-Shuang; Zhao, Kai; Chen, Quan-Jiao; Deng, Fei; Liu, Lin-Lin; Yan, Bing; Zhan, Fa-Xian; Wang, Yan-Yi; Xiao, Geng-Fu; Shi, Zheng-Li (2020). "A pneumonia outbreak associated with a new coronavirus of probable bat origin". Nature. 579 (7798): 270–273. doi:10.1038/s41586-020-2012-7. ISSN 0028-0836.
- ↑ Decaro N, Mari V, Elia G, Addie DD, Camero M, Lucente MS, Martella V, Buonavoglia C (January 2010). "Recombinant canine coronaviruses in dogs, Europe". Emerging Infect. Dis. 16 (1): 41–7. doi:10.3201/eid1601.090726. PMC 2874359. PMID 20031041.
- ↑ Weiss SR, Navas-Martin S (December 2005). "Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus". Microbiol. Mol. Biol. Rev. 69 (4): 635–64. doi:10.1128/MMBR.69.4.635-664.2005. PMC 1306801. PMID 16339739.
- ↑ Seah, Ivan; Su, Xinyi; Lingam, Gopal (2020). "Revisiting the dangers of the coronavirus in the ophthalmology practice". Eye. 34 (7): 1155–1157. doi:10.1038/s41433-020-0790-7. ISSN 0950-222X.
- ↑ Mathewson, Alison C.; Bishop, Alexandra; Yao, Yongxiu; Kemp, Fred; Ren, Junyuan; Chen, Hongying; Xu, Xiaodong; Berkhout, Ben; van der Hoek, Lia; Jones, Ian M. (2008). "Interaction of severe acute respiratory syndrome-coronavirus and NL63 coronavirus spike proteins with angiotensin converting enzyme-2". Journal of General Virology. 89 (11): 2741–2745. doi:10.1099/vir.0.2008/003962-0. ISSN 0022-1317.
- ↑ Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M (November 2003). "Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus". Nature. 426 (6965): 450–4. doi:10.1038/nature02145. PMC 7095016 Check
|pmc=value (help). PMID 14647384. - ↑ Schoeman, Dewald; Fielding, Burtram C. (2019). "Coronavirus envelope protein: current knowledge". Virology Journal. 16 (1). doi:10.1186/s12985-019-1182-0. ISSN 1743-422X.
- ↑ Fehr, Anthony R.; Perlman, Stanley (2015). "Coronaviruses: An Overview of Their Replication and Pathogenesis". 1282: 1–23. doi:10.1007/978-1-4939-2438-7_1. ISSN 1064-3745.
- ↑ McBride R, van Zyl M, Fielding BC (August 2014). "The coronavirus nucleocapsid is a multifunctional protein". Viruses. 6 (8): 2991–3018. doi:10.3390/v6082991. PMC 4147684. PMID 25105276.
- ↑ Mathewson, Alison C.; Bishop, Alexandra; Yao, Yongxiu; Kemp, Fred; Ren, Junyuan; Chen, Hongying; Xu, Xiaodong; Berkhout, Ben; van der Hoek, Lia; Jones, Ian M. (2008). "Interaction of severe acute respiratory syndrome-coronavirus and NL63 coronavirus spike proteins with angiotensin converting enzyme-2". Journal of General Virology. 89 (11): 2741–2745. doi:10.1099/vir.0.2008/003962-0. ISSN 0022-1317.
- ↑ Zhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang; Hu, Ben; Zhang, Lei; Zhang, Wei; Si, Hao-Rui; Zhu, Yan; Li, Bei; Huang, Chao-Lin; Chen, Hui-Dong; Chen, Jing; Luo, Yun; Guo, Hua; Jiang, Ren-Di; Liu, Mei-Qin; Chen, Ying; Shen, Xu-Rui; Wang, Xi; Zheng, Xiao-Shuang; Zhao, Kai; Chen, Quan-Jiao; Deng, Fei; Liu, Lin-Lin; Yan, Bing; Zhan, Fa-Xian; Wang, Yan-Yi; Xiao, Geng-Fu; Shi, Zheng-Li (2020). "A pneumonia outbreak associated with a new coronavirus of probable bat origin". Nature. 579 (7798): 270–273. doi:10.1038/s41586-020-2012-7. ISSN 0028-0836.
- ↑ Nieva, José; Carrasco, Luis (2015). "Viroporins: Structures and functions beyond cell membrane permeabilization". Viruses. 7 (10): 5169–5171. doi:10.3390/v7102866. ISSN 1999-4915.
- ↑ Schoeman, Dewald; Fielding, Burtram C. (2019). "Coronavirus envelope protein: current knowledge". Virology Journal. 16 (1). doi:10.1186/s12985-019-1182-0. ISSN 1743-422X.
- ↑ Schoeman, Dewald; Fielding, Burtram C. (2019). "Coronavirus envelope protein: current knowledge". Virology Journal. 16 (1). doi:10.1186/s12985-019-1182-0. ISSN 1743-422X.
- ↑ Schoeman, Dewald; Fielding, Burtram C. (2019). "Coronavirus envelope protein: current knowledge". Virology Journal. 16 (1). doi:10.1186/s12985-019-1182-0. ISSN 1743-422X.
- ↑ Siu, Y. L.; Teoh, K. T.; Lo, J.; Chan, C. M.; Kien, F.; Escriou, N.; Tsao, S. W.; Nicholls, J. M.; Altmeyer, R.; Peiris, J. S. M.; Bruzzone, R.; Nal, B. (2008). "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". Journal of Virology. 82 (22): 11318–11330. doi:10.1128/JVI.01052-08. ISSN 0022-538X.
- ↑ Tooze J, Tooze S, Warren G (March 1984). "Replication of coronavirus MHV-A59 in sac- cells: determination of the first site of budding of progeny virions". Eur. J. Cell Biol. 33 (2): 281–93. PMID 6325194.
- ↑ McBride R, van Zyl M, Fielding BC (August 2014). "The coronavirus nucleocapsid is a multifunctional protein". Viruses. 6 (8): 2991–3018. doi:10.3390/v6082991. PMC 4147684. PMID 25105276.
- ↑ Kubo H, Yamada YK, Taguchi F (September 1994). "Localization of neutralizing epitopes and the receptor-binding site within the amino-terminal 330 amino acids of the murine coronavirus spike protein". J. Virol. 68 (9): 5403–10. PMC 236940. PMID 7520090.
- ↑ Zhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang; Hu, Ben; Zhang, Lei; Zhang, Wei; Si, Hao-Rui; Zhu, Yan; Li, Bei; Huang, Chao-Lin; Chen, Hui-Dong; Chen, Jing; Luo, Yun; Guo, Hua; Jiang, Ren-Di; Liu, Mei-Qin; Chen, Ying; Shen, Xu-Rui; Wang, Xi; Zheng, Xiao-Shuang; Zhao, Kai; Chen, Quan-Jiao; Deng, Fei; Liu, Lin-Lin; Yan, Bing; Zhan, Fa-Xian; Wang, Yan-Yi; Xiao, Geng-Fu; Shi, Zheng-Li (2020). "A pneumonia outbreak associated with a new coronavirus of probable bat origin". Nature. 579 (7798): 270–273. doi:10.1038/s41586-020-2012-7. ISSN 0028-0836.
- ↑ Belouzard S, Chu VC, Whittaker GR (April 2009). "Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites". Proc. Natl. Acad. Sci. U.S.A. 106 (14): 5871–6. doi:10.1073/pnas.0809524106. PMC 2660061. PMID 19321428.
- ↑ Knuhtsen S, Holst JJ, Schwartz TW, Jensen SL, Nielsen OV (May 1987). "The effect of gastrin-releasing peptide on the endocrine pancreas". Regul. Pept. 17 (5): 269–76. doi:10.1016/0167-0115(87)90284-9. PMID 2885899.
- ↑ Sethna PB, Hofmann MA, Brian DA (January 1991). "Minus-strand copies of replicating coronavirus mRNAs contain antileaders". J. Virol. 65 (1): 320–5. PMC 240520. PMID 1985203.
- ↑ Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, Yu J, Kang M, Song Y, Xia J, Guo Q, Song T, He J, Yen HL, Peiris M, Wu J (March 2020). "SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients". N. Engl. J. Med. 382 (12): 1177–1179. doi:10.1056/NEJMc2001737. PMC 7121626 Check
|pmc=value (help). PMID 32074444 Check|pmid=value (help). - ↑ Zheng J (2020). "SARS-CoV-2: an Emerging Coronavirus that Causes a Global Threat". Int. J. Biol. Sci. 16 (10): 1678–1685. doi:10.7150/ijbs.45053. PMC 7098030 Check
|pmc=value (help). PMID 32226285 Check|pmid=value (help). - ↑ Puelles VG, Lütgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, Chilla S, Heinemann A, Wanner N, Liu S, Braun F, Lu S, Pfefferle S, Schröder AS, Edler C, Gross O, Glatzel M, Wichmann D, Wiech T, Kluge S, Pueschel K, Aepfelbacher M, Huber TB (May 2020). "Multiorgan and Renal Tropism of SARS-CoV-2". N. Engl. J. Med. doi:10.1056/NEJMc2011400. PMC 7240771 Check
|pmc=value (help). PMID 32402155 Check|pmid=value (help). - ↑ Puelles VG, Lütgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, Chilla S, Heinemann A, Wanner N, Liu S, Braun F, Lu S, Pfefferle S, Schröder AS, Edler C, Gross O, Glatzel M, Wichmann D, Wiech T, Kluge S, Pueschel K, Aepfelbacher M, Huber TB (May 2020). "Multiorgan and Renal Tropism of SARS-CoV-2". N. Engl. J. Med. doi:10.1056/NEJMc2011400. PMC 7240771 Check
|pmc=value (help). PMID 32402155 Check|pmid=value (help).