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Compared to other coronaviruses (SARS-CoV and HCoV-NL63), SARS-CoV-2 spreads much more efficiently in a short time although all three coronaviruses use the same receptor to enter the cell and infect it. In this study, the researchers compared SARS-CoV-2 and HCoV-NL63 in model human airway cells to better understand what makes SARS-CoV-2 spread more easily. They found that SARS-CoV-2 replicates in the cell differently, is able to infect more types of cells and leads to more cell death than HCoV-NL63.
Researchers have made a lot of progress when it comes to understanding SARS-CoV-2, the virus that causes COVID-19. That being said, there are still things about SARS-CoV-2 that we don’t fully understand yet. We know that the virus can be spread from person to person quickly and easily, but some of the key details on how it makes copies of itself in the body aren’t known yet. Compared to other coronaviruses that have been researched, SARS-CoV-2 seems to be very different and unique in the way that it infects human cells, particularly human airway epithelial (HAE) cells and replicates. This study is important because it gives us information on how the virus infects and copies itself in human cells and its harmful effects.
So let’s get into it.
Experiment and Results:
The researchers compared SARS-CoV-2 infections to HCoV-NL63 (a different type of coronavirus) infections in model human cells, HAE, to better understand what makes SARS-CoV-2 unique. Here’s what they found:
1. SARS-CoV2 replicates differently than HCoV-NL63 in HAE cells.
SARS-CoV-2 and HCoV-NL63 were added to human airway cells to assess how the virus replicates. Researchers found that the cells were more easily infected by SARS-CoV-2. The highest rate of new virus particle production was at 48–72 h post infection. This is fast compared to the 72–96 h benchmark for HCoV-NL63, suggesting that SARS-CoV-2 is able to replicate more efficiently than the other coronavirus . SARS-CoV-2 also showed higher viral titers than HCoV-NL63 which means more SAR-CoV-2 was released from the cells and into the surrounding area as the infection progressed while almost no HCoV-NL63 was released into the surrounding area post infection. Thus, SARS-CoV-2 spreads itself throughout the body more efficiently and can enter close-by cells and cause further infection. Researchers also measured the strength of the thin flexible layer around the cells (membrane) using a Volt-Ohm Meter and found that, at 96 hours post infection, the cells infected with SARS-CoV-2 had a 40% reduction in their membrane strength compared to no reduction in HCoV-NL63 infection. The decrease in membrane strength was accompanied by an increase in viral particles outside the cell. This suggests that SARS-CoV-2 is able to degrade the membrane, weakening it, to make it easier for the viral particles to break out of the cell and spread into the surrounding area.
2. SARS-CoV-2 has a host cell range than other coronaviruses in the human airway epithelium.
In a previous study, coronaviruses, such as SARS-CoV-2, SARS-CoV, and HCoB-NL63, were all shown to use the same cell receptor, ACE2, to enter specific cells. From this, researchers wanted to confirm which cells SARS-CoV-2 is able to replicate in and if it has more than one specific cell reporter, Using microscopy, it was found that SARS-CoV-2 infects two kinds of cells in the respiratory tract: ciliated cells and secretory cells. These cells are what make up the airway in humans and they are very important cells. These cell types can protect us from viruses and bacteria by killing and removing them from the body. What’s interesting is that this makes SARS-CoV-2 dramatically different from the six other human coronaviruses. Other coronaviruses usually can only infect one of these types of cells, but not both. What does this mean? This means that SARS-CoV-2 might be able to use a wider range of cell surface receptors to attach to and enter the cells. This can explain why the SARS-CoV-2 is so infectious; it is able to attack and enter more cells than other coronaviruses.
3. Structural changes in HAE resulting from SARS-CoV-2 viral infection.
Plaque-like structures were observed in SARS-CoV-2-infected cells by microscopy and staining, in other words, the morphology of the infected cells changed drastically. The size and number of plaques increased the longer the virus was in the cell. Further research showed giant multinuclear cell (cells with more than one nucleus) formations and destruction of cell tight junctions. Tight junctions are areas where the membranes of two adjacent cells join together to form a barrier. One of the roles of tight junctions is to prevent molecules from passing in between the cells. Additionally, small hair-like projections that move microbes and debris up and out of the airways (cilia), were shrunken and disordered in SARS-CoV-2-infected cells. Researchers also found numerous membranous and usually fluid-filled pouches (vesicles) in the area between the cell membrane and the nucleus known as the cytoplasm, which were similar to those caused by other coronavirus infections. There was also a large amount of cell death and gathering of organelles close to the cell surface. From this, the authors of the papers concluded that SARS-CoV-2 induced cell death (apoptosis).
The ability of SARS-CoV-2 to infect both ciliated cells and secretory cells suggests that SARS-CoV-2 may use other receptors (beyond ACE2) to enter the cell. SARS-CoV-2 was found to replicate better in human airway cells than other coronaviruses which is a possible explanation for why SARS-CoV-2 spreads so easily. Another reason this virus may spread so easily is its ability to infect both ciliated cells and secretory cells. Furthermore, the secretory cells released vesicles with large amounts of viral particles. This explains the high detection rate of SARS- CoV-2 in mucus and its spreading by droplets. The disruption of cilia by SARS- CoV-2 leads to poor mucus and airway clearance, making it easier for the infection to spread further.
The data together suggests that SARS-CoV-2 is fully adapted to the human airway, which is distinct from other coronaviruses.
This was an important study to show how different SARS-CoV-2 is from other coronaviruses in terms of its replication and its broader host cell range. Though, this study only scrapped the surface of the main question, which is how does SARS-CoV-2 replicate better and cause more pathology than other coronaviruses? To answer this question, researchers could have gone beyond what they did and examined the immune response of the infected cells. This might give us a better idea if this virus causes the immune response to be weaker or if there is something about the viral mechanism that makes it more virulent. Other specific work is also needed, such as looking at what other cell receptors does this specific virus have that other coronaviruses don’t. Additionally, looking into the different genes and proteins of the virus and trying to determine what specific part of the virus causes these cellular effects and fast replication can differently help understand how to create better clinical treatment and prevention methods.