SARS-CoV-2 Coronavirus: Structure, Genome, Proteins, Replication, Pathogenesis, and Host Interaction

Coronavirus Overview

• Coronaviruses (CoVs) are enveloped viruses (surrounded by a lipid membrane derived from host cells), belonging to the subfamily Coronavirinae, family Coronaviridae, order Nidovirales.
• They are positive-sense, single-stranded RNA viruses (ssRNA(+), meaning their RNA can directly act as mRNA for translation).
• Coronaviruses are divided into four genera:
• Alphacoronavirus (αCoV) – typically found in bats and rodents, some cause human respiratory infections.
• Betacoronavirus (βCoV) – includes SARS-CoV, MERS-CoV, SARS-CoV-2.
• Deltacoronavirus (δCoV) – mainly in avian species.
• Gammacoronavirus (γCoV) – also predominantly avian.
• Most CoVs are zoonotic, meaning they originate in animals and can jump to humans, which makes them a major concern for emerging infectious diseases.

Structure of SARS-CoV-2

• SARS-CoV-2 is a betacoronavirus, an enveloped, positive-sense, single-stranded RNA virus.
• Virions are spherical to pleomorphic, measuring 80–160 nm in diameter.
• Major structural proteins:
1. Spike (S) protein – a glycoprotein that protrudes from the viral envelope, forming the characteristic crown-like appearance (corona) and mediating *host cell entry.
2. Membrane (M) protein – the most abundant structural protein, defines the shape of the viral envelope, and interacts with the nucleocapsid (N) protein to organize assembly.
3. Envelope (E) protein – the smallest structural protein, involved in viral assembly, budding, and pathogenesis, and acts as an ion channel (viroporin).
4. Nucleocapsid (N) protein – binds to viral RNA to form the helical nucleocapsid, assists in viral RNA packaging, transcription regulation, and modulates host immune response.
• Transmembrane proteins (S and M) help the virus anchor into the lipid envelope and facilitate virus assembly during replication.

Spike Glycoprotein (S protein)

• Comprised of S1 and S2 subunits:
• S1 subunit: contains a signal peptide, N-terminal domain (NTD), and receptor-binding domain (RBD). The RBD binds specifically to ACE2 receptors (Angiotensin-converting enzyme 2) on human respiratory epithelial cells.
• S2 subunit: contains the fusion peptide, heptad repeats (HR1 & HR2), transmembrane domain, and cytoplasmic tail, essential for fusion of viral and host membranes.
• Function: Spike protein mediates host recognition, attachment, and entry, which is critical for viral infectivity.
• Host receptor binding: SARS-CoV-2 binds ACE2 with higher affinity than SARS-CoV, explaining its enhanced transmission.
• After binding, the viral envelope fuses with the host membrane, releasing the viral RNA genome into the cytoplasm.

Genomic Organization

• SARS-CoV-2 has a positive-sense RNA genome of ~30 kb (29,891 nucleotides), encoding 9,860 amino acids, with G+C content ~38%.
• Genome features:
• 12 functional ORFs (open reading frames)
• 9 subgenomic mRNAs
• 5′ and 3′ untranslated regions (UTRs) – regulatory regions for replication and transcription.
• Major ORFs:

1. ORF1a and ORF1b – encode polyproteins pp1a and pp1ab, processed into 16 non-structural proteins (NSPs).
2. Remaining ORFs encode structural proteins (S, E, M, N) and accessory proteins, which help the virus evade host immunity.

Key Enzymes and Proteins

1. NSP3 – Papain-like protease
• Function: Cleaves viral polyproteins into functional NSPs and suppresses host immune response by deubiquitination.
2. NSP5 – Main protease (Mpro)
• Function: Processes viral polyproteins at multiple sites; essential for viral replication.
3. NSP12 – RNA-dependent RNA polymerase (RdRp)
• Function: Catalyzes replication of viral RNA, synthesizing complementary negative-sense RNA as a template for progeny genomes.
4. NSP13 – Helicase
• Function: Unwinds viral RNA secondary structures during replication and transcription.
5. Accessory proteins
• Function: Interfere with host innate immunity, particularly type I interferon response, facilitating immune evasion.

Replication Cycle

1. Attachment: Spike protein binds ACE2 receptor → endocytosis or membrane fusion.
2. Uncoating: Release of viral RNA into cytoplasm.
3. Translation of ORF1a/1b: Polyproteins pp1a/pp1ab are synthesized and cleaved by viral proteases (NSP3 & NSP5) into functional NSPs.
4. Replication: RdRp (NSP12) synthesizes negative-sense RNA, used as a template for new positive-sense RNA and subgenomic mRNAs.
5. Translation of structural proteins: S, M, E, N are translated and processed through ER-Golgi network.
6. Assembly: Nucleocapsid (RNA + N protein) binds M protein at ERGIC (endoplasmic reticulum-Golgi intermediate compartment).
7. Budding and Release: Virions bud into ERGIC vesicles → transported via Golgi → released by exocytosis.

Pathogenesis

• Transmission: Respiratory droplets, aerosols, and contact with contaminated surfaces.
• Tropism: Respiratory epithelium (high ACE2 expression).
• Cellular effects: Viral replication leads to ciliostasis (loss of ciliary movement), cell death, and inflammatory cytokine production.
• Severe infection can involve lungs, heart, kidneys, and brain, causing multi-organ failure in critical cases.

Host Interaction

• Immune evasion: Accessory proteins suppress type I interferons, reducing early antiviral response.
• Spike protein: High-affinity binding to ACE2 increases viral entry efficiency.
• Cytokine storm: Overactivation of immune system can lead to tissue damage and ARDS (acute respiratory distress syndrome).