Introduction
In the last post, we presented the general information about SARS-CoV-2 & COVID-19, like the taxonomical classification, structure, symptoms and precautions. In this and the next post, we will describe about the life cyle of the virus.
Here we go:
Life cycle of SARS-CoV-2
As we saw in the last post, SARS-CoV-2 (fig 1) belongs to the family of viruses called as Coronaviridae. These viruses are zoonotic and can infect and cause diseases in the birds and mammals including humans. These viruses are continuously mutating and evolving to produce different symptoms or infecting newer hosts. Such evolution in SARS-CoV-2 gave it the ability to attach and infect the human cells.
Attachment:
The SARS-CoV-2 has spikes (previous post) , which are homotrimers of S proteins (fig 2A). S protein have two functional subunits S1 and S2 (fig 2B & 2C).
The S1 subunit has the Receptor Binding Domain (RBD), whose 394-glutamine residue, interacts with the lysine 31 residue of the host surface protein, human angiotensin-converting enzyme 2 (hACE2). This interaction is very strong and anchors the virus onto the host cell.
(Just for info: Read this paper titled ‘Angiotensin-I-converting enzyme and its relatives’)
Entry:
After the attachment of the S protein to the hACE2 protein, the S protein is cleaved at S1/S2 and the S2’ site by the host proteases (see fig 3). SARS-CoV-2 can use two different proteases; namely endosomal cysteine proteases cathepsin B & L (CatB/L) and cellular serine protease TMPRSS2 for S protein cleavage.
The first cleavage at the S1/S2 boundary separates the RBD and fusion domain of the S protein. Then, the next cleavage at S2′, exposes a fusion peptide, that brings about the fusion of the two membranes, and the viral genome is released into the host cytoplasm (see fig 3).
-RNA genome.
The genome of SARS-CoV-2 consists of non-segmented, positive-sense RNA of around 29.9 kb. The SARS-CoV-2 genome has a 5′ cap structure and 3′ poly (A) tail, allowing it to act as a mRNA for viral proteins synthesis.
The genes are organised in a order as:
5′- leader – UTR – replicase – S (Spike) – E (Envelope) – M (Membrane) – N (Nucleocapsid) – 3′UTR-poly (A) tail.
The accessory genes are interspersed within the structural genes (Fig 4).
The 5′ end of the genome has a leader sequence and untranslated region (UTR), having stem loop structures needed for RNA replication and transcription.
Downstream to the 5’UTR, are two open reading frames (ORFs), ORF1a and ORF1b, which together occupy around 2/3rd of the viral genome. These two overlapping ORFs, together make up the gene for replicase, encoding two polyproteins; pp1a and pp1ab. The two polyproteins are cleaved by viral proteases into 16 different non-structural proteins (nsps). The non-structural genes play important role in the replication and the transcription of the genome (and not viral structure).
The structural and accessory (interspersed between structural proteins) proteins, make up the remaining 1/3rd (about 10 kb) of the viral genome. The structural proteins make up the virion particles and the accessory proteins are required for the viral pathogenesis.
There is another important sequence, at the downstream of the 5’UTR, which is also present at the beginning of each structural or accessory gene, known as transcriptional regulatory sequences (TRSs). These sequences are required for expression of each of these genes.
The 3′UTR also contains RNA structures required for replication and synthesis of viral RNA.
The further steps are Replication and Transciption, Protein synthesis, Assembly and Release of the progeny Virion particles, which we shall see in the second part of the Life cycle of the SARS-CoV-2.
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Just a request,
During this COVID-19 pandemic, stay at home and prevent the spread of this highly contagious virus!!
Be safe!! Be informed!!
And spread the information with your near and dear ones and anyone else!!
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Read other posts by The Biotech Notes:
Clinical Trials (P-2): Randomization.
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References:
Angeletti et al (2020) COVID‐2019: The role of the nsp2 and nsp3 in its pathogenesis Journal of Medical Virology. https://doi.org/10.1002/jmv.25719
Cornillez-Ty et al. (2009) Severe Acute Respiratory Syndrome Coronavirus non-structural protein 2 interacts with a host protein complex involved in mitochondrial biogenesis and intracellular signalling. Journal of Virology: 10314-10318.
Fehr and Perlman. (2015) Coronaviruses: An Overview of Their Replication and Pathogenesis. Methods Mol Biol. 1282: 1–23. doi:10.1007/978-1-4939-2438-7_1.
Graham et al. (2008) SARS coronavirus replicase proteins in pathogenesis. Virus Res. 133(1): 88–100.
Hagemeijer et al.( 2012) Biogenesis and Dynamics of the Coronavirus Replicative Structures. Viruses 4:3245-3269. doi:10.3390/v4113245.
Hoffman et al. (2020) SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Hoffmann et al., SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell 181:1–10, https://doi.org/10.1016/j.cell.2020.02.052
Masters (2019) Virology, Coronavirus genomic RNA packaging. Virology 537: 198-207.
Maxwell (2014) Structural determinants of Coronavirus nsp5 function and inhibition. Thesis submitted to Vanderbilt University.
Nakagawa et al (2016) Viral and Cellular mRNA Translation in Coronavirus-Infected Cells. Adv Virus Res. 96:165–192. doi:10.1016/bs.aivir.2016.08.0
Walls et al (2020) Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein [published online ahead of print]. Cell doi:10.1016/j.cell.2020.02.058
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