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How Does the SARS-CoV-2 Virus Enter Your Cells?

How Does the SARS-CoV-2 Virus Enter Your Cells?

A virus, from the Latin word for “poison” or “slimy liquid,” refers to a small infectious agent that is capable of replication only through inhabiting living host cells prior to viral replication, like those of bacteria, plants, and animals. They’re ubiquitous, and can be found in nearly every crevice on Earth. Remnants of millions of years’ worth of viral infections in our ancestors can be seen in our very genetic makeup today; around 8% of all the DNA you have on you right now were probably remnants of ancient viruses, cemented in place after your ancestors’ cells were hijacked so long ago.

Of course, any discussion regarding viruses in times like these will likely point towards the timely topic of the past two years: the COVID-19 pandemic, caused by a runaway spread of the SARS-CoV-2 virus. Of particular interest at the time of writing is the B.1.617.2 variant of the virus, colloquially known as the Delta variant of the virus. After surfacing from India during the latter half of 2020, the virus has now spread to nearly all parts of the globe, impacting at least 142 countries as of August 10. Several studies have shown its effectiveness at infecting, and spreading across, a population. It’s unfortunate ubiquity, then, begs the question: how does a SARS-CoV-2 virus enter a human cell in the first place?

The Mechanism

This cross-sectional image of a single SARS-CoV-2 virion. (Granet, 2021)

The typical SARS-CoV-2 virus looks like a ball with little darts dotting its outer layer, like in the image above. Its key features include the functional viral genome, the viral membrane protein (M), the envelope protein (E), and the spike protein (S). Inside the “ball” is the viral genome; the goal of the virus is to replicate this genomic sequence and encase it in another membrane, ready for infection to other sites, either within the body or beyond it. The spike protein is then separated into two functional areas, labeled S1 and S2. S1 contains the “head” of the spike protein, all the way down to what is called the cleavage site. S2, on the other hand, starts from below the site all the way down to where it joins the viral envelope.

Once SARS-CoV-2 enters your body, it may find itself attached to an inner lining somewhere inside, like a respiratory tract, gastrointestinal tract, or blood vessels—essentially any internal surface on your body that expresses the angiotensin converting enzyme 2, also known as ACE2. (Regularly, ACE2 is responsible for cutting apart the angiotensinogen protein into smaller proteins, making these smaller proteins available for cell regulatory function.)

Shown here are the two possible pathways for the SARS-CoV-2 virus to enter your cell prior to viral replication. The pathways progress depending on the presence of proteases near where the viral spike protein attached itself to an ACE2 site on the host cell’s surface. (Granet, 2021)

Once SARS-CoV-2 has attached itself to an ACE2 site on a cell surface, it may progress further to enter your cell via two possible pathways. These pathways depend on whether or not the virus finds itself in the presence of human protease enzymes, or enzymes that facilitate the breakdown of proteins into smaller subunits like amino acids and polypeptides. These proteases “prime” the viral spike protein, which defines whether it enters your cell one way or the other. Proteases capable of priming the SARS-CoV-2 spike protein include furin, elastase, trypsin, and transmembrane serine proteinase 2 (TMPRSS2). TMPRSS2 can usually be found expressed by cells in the lungs, which experts think is one of the reasons why SARS-CoV-2 has an affinity for infecting respiratory cells.

When Proteases Are Near

If there happens to be a protease present near the spike protein-ACE2 anchor site, the protease “cleaves” the spike protein at the cleavage site. This exposes the S2 region of the spike protein, which happens to contain hydrophobic or lipid-like regions like the fusion peptide region. (Hydrophobicity refers to the property of the viral region to have an affinity towards repelling water, given the arrangement of its molecules.)

The lipid-like ends of the spike protein mimic the lipid-containing cell membrane. This way, the cell thinks it is merely “absorbing” one of its own, initiating the merging of the viral membrane into the cell membrane. From there, the viral genome has successfully entered the cell, where future processes leave it free to express its instructions for the cell to perform, such as replication.

In the Absence of Proteases

Should there be no nearby proteases to start the cleaving of the spike protein, the SARS-CoV-2 virus instead enters the host cell through a process known as endocytosis. The process begins in small indentations present in the surface of the infected cell; from here, the host cell slowly engulfs the virus, then closing it off to form a bubble-like structure known as an endocytic vesicle.

Now, inside the cell are other bubble-like structures, this time bounded by material from the inner cellular membrane of the cell, called endosomes. The endocytic vesicle fuses with the endosome while inside the host cell. Unfortunately, the endosome, much like the surface of the cell, also contains proteases. One protease inside endosomes, called cathepsin L, is also capable of cleaving SARS-CoV-2’s spike protein; once it does, the same fusion peptide region becomes exposed to the surrounding inner cell membrane. From here, the fusion peptides facilitate the merging of the viral membrane into the endosome membrane, followed by the successful entry of the viral genome into the host cell.

Other Pathways

Recent studies, like the SARS-CoV-2 cell entry mechanism study by Shang and co-authors in the journal Proceedings of the National Academy of Sciences back in 2020, propose a possible third mechanism of entry for SARS-CoV-2 into host cells. In it, they propose that as a “hijacked” cell begins viral replication, some of the spike proteins of the new viruses produced may be “pre-primed” by the protease furin; this means that the viruses produced will no longer have to wait for the presence of proteases in its future potential hosts before initiating membrane fusion. From there, the process goes along as described.

We Are Fighting Back

Researchers are hard at work finding new ways of nipping this infection problem for SARS-CoV-2 at the bud. One study, described by Chemical Abstracts Service (CAS) information scientist Angela Zhou in an article dated last April 16, details the use of soluble ACE2 as a way to possibly “deactivate” the spike protein by binding to it before it finds a cell with a normal ACE2 site on its surface. Other methods currently under research involve inhibiting the proteases responsible for initiating the cell- and viral-membrane merger.

Overall, experts are well underway in researching how we can stop the progression of SARS-CoV-2 entry into our cells, either by hitting its spike protein, inhibiting our ACE2 sites, or inhibiting the protease enzymes on our cells. Several other approaches are also being explored by scientists to help curb the spread of COVID-19 through medication, alongside the development and refinement of vaccines that help teach our antibodies how to fight the SARS-CoV-2 virus as it enters our body. After all, the fight against COVID-19 continues, as the concerted joint effort of medical and occupational frontliners, researchers, and citizens slowly work their way into taking down the threat of this virus once and for all.

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