SARS-CoV-2 is the pathogen responsible for COVID-19. Like all viruses, it is an obligate intracellular parasite, meaning it cannot reproduce on its own. It must invade a living host cell and take over the cell’s machinery to create new copies of itself. This process begins with specific recognition of the host cell surface and unfolds through a series of steps, starting with entry and culminating in the production and release of new infectious particles.
The Key to the Cell: Spike Protein and ACE2 Receptor
The initial step of infection relies on a molecular interaction. The “key” is the viral Spike (S) protein, which protrudes from the virus surface. The “lock” is the Angiotensin-Converting Enzyme 2 (ACE2) receptor, a protein found on the surface of many human cells, particularly those in the respiratory tract, heart, and blood vessels.
The Spike protein has two subunits, S1 and S2. The S1 subunit contains the Receptor-Binding Domain (RBD), which directly engages with the ACE2 receptor on the host cell membrane. This tight connection initiates the entry process. The strong binding affinity of the Spike protein for ACE2 contributes to the virus’s high infectivity.
To gain entry, the Spike protein must be activated by host cell enzymes, such as the transmembrane protease serine 2 (TMPRSS2). This enzyme cleaves the Spike protein, triggering a shape change required for membrane fusion. This cleavage exposes a fusion peptide within the S2 subunit, allowing the viral envelope to merge with the host cell membrane.
Once the membranes fuse, the virus’s genetic material is released directly into the cell’s cytoplasm. Alternatively, the cell may internalize the entire virus particle through endocytosis. In this case, the viral envelope fuses with the membrane of the internal vesicle (endosome) to release the genetic cargo.
Hijacking the Factory: RNA Replication and Protein Synthesis
Upon entry, the viral capsule dissolves (uncoating), releasing the positive-sense single-stranded RNA (+ssRNA) genome into the host cell cytoplasm. This viral RNA is similar to the cell’s messenger RNA (mRNA) and is immediately recognized by the host’s ribosomes. The hijacked host cell machinery begins translating the viral genome.
The first proteins produced are the non-structural proteins (nsps), translated as two long polyproteins, pp1a and pp1ab. Viral-encoded proteases then cut these chains into 16 smaller proteins. The most important of these is the RNA-dependent RNA Polymerase (RdRp), also known as nsp12.
The RdRp, along with cofactors like nsp7 and nsp8, forms the core of the Replication-Transcription Complex (RTC). The RTC establishes specialized structures, often double-membrane vesicles, where RNA synthesis occurs, shielded from host immune sensors. The RTC performs two functions: replication and transcription.
Replication creates full-length copies of the viral genome for new virions. The RdRp first synthesizes a complementary negative-sense RNA strand using the original positive-sense genome as a template. This negative-sense intermediate then serves as the template to produce thousands of new positive-sense genomic RNA copies.
Transcription generates multiple smaller messenger RNA molecules, called sub-genomic RNAs (sgRNAs). Host ribosomes translate these sgRNAs to produce the four structural proteins:
- Spike (S)
- Envelope (E)
- Membrane (M)
- Nucleocapsid (N)
Replication and transcription provide all the necessary components—new genomes and structural proteins—to build new infectious virus particles.
Packaging and Exit: Assembling New Virions
Once viral components are produced, the final phase begins with assembly and packaging. The newly synthesized structural proteins (Spike, Membrane, and Envelope) are directed toward the Endoplasmic Reticulum (ER) and then traffic to the ER-Golgi Intermediate Compartment (ERGIC). These proteins insert into the membranes of these compartments, marking the location where new virions will bud.
Simultaneously, the replicated full-length positive-sense genomic RNA complexes with the Nucleocapsid (N) protein in the cytoplasm. The N protein coats the RNA strand, forming the helical nucleocapsid core. This core is transported to the ERGIC membrane where the structural proteins are clustered.
Assembly occurs as the nucleocapsid core interacts with the Membrane protein, driving the budding of the new virion into the lumen (interior space) of the ERGIC. The viral particle acquires its protective lipid envelope during this process, studded with the Spike, Membrane, and Envelope proteins. This step ensures the correct incorporation of all viral components into a fully infectious particle.
The assembled virions, trapped within transport vesicles, are transported through the host cell’s secretory pathway. These vesicles migrate toward the cell surface and the plasma membrane. Finally, the vesicles fuse with the outer cell membrane, releasing the infectious SARS-CoV-2 particles outside the cell via exocytosis. These virions are then free to infect neighboring host cells, propagating the infection.