How SARS-CoV-2 Infects Host Cells
Scientists across the world are racing to find treatments and vaccinations for COVID-19, the disease caused by the virus SARS-CoV-2. While many treatments are being considered, some potential treatments focus specifically on finding a way to block the entry of the virus into host cells. For these drugs to be developed, however, we first need to understand the mechanisms SARS-CoV-2 uses to enter and infect host cells.
Coronaviruses such as SARS-CoV-2 get their name from their crown-like structure; the virus is shaped like a ball with spikes jutting out from the surface. These “spikes” are protein trimers which are composed of two protein subunits, S1 and S2. S1 (a receptor binding head at the top of the spike) and S2 (the stalk of the spike) directly interact with human host cells to allow the virus’ entry.
The S1 subunit of the spike contains a receptor-binding domain (RBD) that will bind to an enzyme (ACE2, or hACE2 in humans) on the host cell membrane. The RBD can switch between a standing-up position for binding and a lying-down position for immune system evasion. In SARS-CoV-2, this RBD is typically found in the down position. While this makes it more difficult for the RBD to bind to ACE2, it makes it easier to remain undetected by the immune system. When RBDs hide from the immune system, it is more difficult for neutralizing antibodies to bind to the virus and block it from entering cells.
During entry into a cell, the virus’ RBD binds to the host cell’s ACE2. Once the two are bound, the spike proteins on the virus will be activated by proteases on the hostcell’s surface. Proteases are enzymes that can cleave specific proteins. The virus’ S1 protein is cleaved by two proteases to facilitate entry. The cleavage leads to a structural change in S2 that allows the virus membrane to fuse with the host cell membrane. After the membranes have fused, genetic material from the virus will replicate inside the host cell, leading to infection.
Photo: SARS-CoV-2 spike receptor binding-domain, ACE2 complex (Click to enlarge).
- ACE2 is an enzyme attached to the outer surface (cell membrane) of cells in the lungs, and some other organs. It serves as an entry point into cells for some coronaviruses.
- Protease is an enzyme that breaks down proteins into smaller parts. They are involved in many biological functions, including digestion and communication between cells.
- Furin is an enzyme that helps to remove sections from inactive protein structures to activate them.
- RBD or receptor binding-domain is the part of a protein that has a specific shape, allowing it to bind to a protein with matching shape.
Furin cleavage sites have been found on the surface of the SARS-CoV-2 spike. These sites have been seen to have a major impact on SARS-CoV-2 entry into cells. Furin aids in cleaving S1 and S2, by pre-activating the virus so it can bind to cells without the need of proteases on the host cell’s surface. This increases the efficacy of SARS-CoV-2 in entering cells that may be low in these proteases and makes up for the difficulty in binding caused by a hidden RBD.
SARS-CoV-2 shares some similarities with the SARS-CoV virus that broke out in China in 2002. Both are coronaviruses, so they enter cells in similar ways. While there are slight differences in how well both viruses bind to the host cell, overall, they enter cells with similar efficacy. However, SARS-CoV-2’s evasive RBD gives it an advantage in avoiding the host’s immune system response.
The location of ACE2 in the human body lends clues as to how this virus enters and spreads in the body. ACE2 is present on many organs; however, it is found in large quantities in the lining of the lungs, nose, mouth, and small intestine. This means that these organs are likely points of entry for the virus. This could also explain why the respiratory and gastrointestinal systems can be severely affected by SARS-CoV-2.
By understanding how and where this virus enters cells in the body, more strategies for how to treat COVID-19 can be formed. Inhibitors could potentially be used to block the proteases and prevent cell entry. Drugs could also be used to block the RBD. The mechanism of entry into the cell provides insight into areas of further interest that could potentially lead to effective COVID-19 treatments.
Jian Shang. “Cell entry mechanisms of SARS-CoV-2.” Proceedings of the National Academy of Sciences of the United States of America (Apr 2020).
Hao Xu. “High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa.” International Journal of Oral Science 12(8) (2020).
I Hamming. “Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.” Journal of Pathology 203(2): 631-637 (2004).
Waradon Sungnak. “SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes.” Nature Medicine 26: 681–687 (2020).
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