The SARS-CoV-2 virus, responsible for the COVID-19 pandemic, infects human cells through a series of intricate steps. This process begins with the virus’s attachment to a cell and culminates in the release of new viral particles. Understanding these biological mechanisms reveals how the virus effectively enters and uses human cellular machinery.
Viral Structure and Key Components
SARS-CoV-2 is an enveloped virus, encased in a lipid membrane derived from its host cell. This membrane surrounds its genetic material, a single strand of positive-sense RNA. Embedded within this viral envelope are three structural proteins: envelope (E), membrane (M), and spike (S). The nucleocapsid (N) protein, the fourth main structural protein, is inside the envelope and encases the viral RNA genome.
The spike (S) protein forms the distinctive crown-like protrusions on the viral surface that give coronaviruses their name. This large glycoprotein has two functional subunits, S1 and S2. The S1 subunit binds to host cell receptors, while S2 facilitates the fusion of viral and host cell membranes. The spike protein is a primary determinant of the virus’s ability to attach and enter human cells.
Cellular Entry Mechanisms
Infection begins when the SARS-CoV-2 spike protein binds to the Angiotensin-converting enzyme 2 (ACE2) receptor on human cells. ACE2 receptors are present on various cell types, including those lining the nasal passages, bronchial tubes, and gastrointestinal tract. This binding positions the virus for entry.
Host cell proteases, notably transmembrane protease serine 2 (TMPRSS2), play a role in enabling viral entry. TMPRSS2 cleaves the spike protein at specific sites, which is necessary for subsequent fusion events. This proteolytic cleavage exposes a fusion peptide within the spike protein, mediating the merging of viral and cellular membranes.
SARS-CoV-2 can enter cells through two main pathways. In cells expressing TMPRSS2, the virus undergoes direct fusion of its membrane with the host cell’s plasma membrane. Alternatively, in cells lacking TMPRSS2, the virus enters through endocytosis, where the host cell engulfs the virus in a vesicle. Both mechanisms lead to the release of the viral genetic material into the host cell’s cytoplasm, initiating infection.
Replication and Assembly Within the Cell
Once the viral RNA genome is inside the host cell’s cytoplasm, the virus rapidly begins to hijack the cell’s internal machinery. Host ribosomes translate specific viral RNA regions, open reading frames 1a and 1ab, into large polyproteins. These extensive protein chains are then cut by viral proteases, yielding individual non-structural proteins (nsps).
Among these non-structural proteins is RNA-dependent RNA polymerase (RdRp), an enzyme essential for viral replication. The virus causes the host cell to create specialized double-membrane vesicles (DMVs) from endoplasmic reticulum membranes. These DMVs provide a protected environment where RdRp synthesizes new copies of the viral RNA genome and transcribes shorter subgenomic RNAs.
Newly produced subgenomic RNAs are translated by host ribosomes to generate the virus’s structural proteins: spike, envelope, membrane, and nucleocapsid. New viral RNA genomes are subsequently packaged with the newly synthesized nucleocapsid proteins. Other structural proteins (S, E, M) are inserted into ER-Golgi intermediate compartment (ERGIC) membranes, where new virions assemble by budding into the ERGIC lumen.
Release of New Viruses
Following assembly within the ERGIC, newly formed SARS-CoV-2 virions are transported through the host cell’s secretory pathway. Exocytosis is the primary mechanism for releasing these new virus particles from the infected cell.
During exocytosis, vesicles containing the virions move to the cell’s outer membrane, where they fuse. This releases mature, infectious virus particles into the extracellular space. The virions acquire their lipid envelope from the host cell’s membranes. The release of these new viruses completes the infection cycle, allowing them to spread and infect neighboring cells or new hosts.