Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, is a positive-sense single-stranded RNA virus belonging to the Betacoronavirus genus. Like all viruses, it is an obligate intracellular parasite, meaning it must gain access to a living host cell to replicate its genetic material and produce new infectious particles. The infection involves a precise sequence of molecular steps, beginning with attachment to the host cell surface and culminating in the release of progeny virions.
Attaching to the Cell: The ACE2 Lock and Key
The initial step of infection relies on a specific interaction between the viral surface and the host cell membrane. SARS-CoV-2 uses its large, club-like Spike (S) protein to attach. The Spike protein features a Receptor-Binding Domain (RBD) that binds to the Angiotensin-Converting Enzyme 2 (ACE2) receptor on the surface of human cells. This binding anchors the virus to the host cell.
Binding to ACE2 alone is not sufficient for entry; the Spike protein must be activated by host cell proteases. The transmembrane serine protease 2 (TMPRSS2), often co-expressed with ACE2 on respiratory epithelial cells, cleaves the Spike protein at a specific site. This proteolytic cleavage, known as priming, exposes a fusion peptide within the Spike protein’s S2 subunit. Once primed, the fusion peptide inserts itself into the host cell membrane, pulling the viral envelope and the host membrane together until they fuse. This fusion allows the viral contents to be released directly into the host cell’s cytoplasm.
Hijacking the Factory: Viral Replication
Once the viral envelope fuses with the host cell membrane, the single-stranded, positive-sense RNA genome is released into the cytoplasm. Host cell ribosomes recognize this RNA as messenger RNA (mRNA) and translate it into a long chain of non-structural proteins (NSPs). Viral proteases within the NSPs then cleave this chain into individual functional proteins needed for the virus’s replication machinery.
The RNA-dependent RNA polymerase (RdRp) forms the catalytic core of the larger Replication-Transcription Complex (RTC). The RTC is a multi-protein assembly that includes accessory proteins like Nsp7, Nsp8, and Nsp13 (a helicase), and is responsible for synthesizing new viral genetic material. This complex operates within specialized double-membrane vesicles (DMVs) created from the host cell’s endoplasmic reticulum, shielding the replication process from immune surveillance. The RdRp uses the original viral RNA as a template to produce full-length copies of the genome (replication) and shorter subgenomic mRNAs (transcription) that are translated to produce the viral structural proteins.
Packaging and Exit: Spreading the Infection
Once the genomic RNA copies and structural proteins are generated, the assembly phase begins. The four main structural proteins—Spike (S), Envelope (E), Membrane (M), and Nucleocapsid (N)—are synthesized by host ribosomes. The S, E, and M proteins are inserted into the Endoplasmic Reticulum (ER) membranes and transported to the ER-Golgi Intermediate Compartment (ERGIC).
The Nucleocapsid (N) protein associates with the full-length genomic RNA in the cytoplasm, condensing it into a helical nucleocapsid structure. This nucleocapsid is transported to the ERGIC where the structural membrane proteins have accumulated. The final virion particle forms when the nucleocapsid buds into the membrane of the ERGIC, acquiring the S, E, and M proteins for its outer envelope. The fully formed virus particles are then released from the infected cell through exocytosis, allowing the progeny virions to exit and seek out new host cells.
The Host Cell’s Fate
The hijacking of the host cell’s machinery ultimately leads to the cell’s destruction, a process that is often tightly regulated. SARS-CoV-2 infection can trigger programmed cell death pathways, including apoptosis (a quieter form of cell death) and pyroptosis (a highly inflammatory form). Pyroptosis is a lytic process where the cell bursts open, which is a host defense mechanism used to deprive the virus of its replicative niche.
This explosive cell death releases various internal components into the surrounding tissue. These components include pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), along with pro-inflammatory molecules like Interleukin-1β and Interleukin-18. The release of these signals activates the immune system’s inflammatory response, recruiting immune cells and leading to the localized inflammation and tissue damage that characterizes the pathology of COVID-19.