Understanding the biology of coronavirus is the key to fighting it. Once we really understand how it works, we will likely be able to design therapies to manage this pandemic.
SARS-CoV2 is a virus. Viruses tend to be just an envelope of different proteins which constitute their body and that also serve other functional purposes like recognizing their targets in the organism they need for replication. In the case of coronavirus, the important point is that it contains a single strand of RNA, which is its genetic material (the equivalent to our DNA) and a protein on its surface (the Spike protein or S-protein), which it uses to bind its target in our cells, which is the Angiotensin-Converting Enzyme 2 (ACE2). The S-protein is actually the structure that gives coronavirus its characteristic crown-like appearance and where its name comes from. ACE2, not to be confused with ACE1 (we will cover this in a later post), is present on the surface of cells of lungs, intestine, blood vessels and others. The distribution of ACE2 in the body determines the preference of SARS-CoV2 for certain tissues like the lungs (hence the respiratory symptomatology) and also the intestine, as well as the means by which it can be transmitted between people (1,2).
Once the virus enters our body (Image, 1), it recognizes its target on our cells (ACE2), binds and enters (Image, 2). Once inside, it hijacks our cell machinery and its genetic material (RNA) is read by human ribosomes to create viral proteins (Image, 3). In fact, there is evidence that the virus may use the ribosomes in our mitochondria, the powerhouses of our cells, to produce its proteins. These are technically not our ribosomes but let us take them as if they were (this has potential therapeutic implications that we will cover in our next post). That the viral genome may be read and translated by human and human-mitochondrial ribosomes is possible because the genetic code is universal, so SARS-CoV2 speaks the same molecular language as we (and our mitochondria) do.
The crucial viral protein created first is the RNA-dependent RNA polymerase (let us just call it viral polymerase). This viral polymerase, despite being created by human cell tools, is highly specific to read the viral RNA and to create multiple copies of the viral original genome (Image, 4). As in the first instance, these new viral genomes can also be read by human ribosomes to make more viral proteins (more viral polymerase) but also others that the virus needs to generate new viruses, like S-protein and the structural ones that will constitute its body when it leaves the cell.
It is important to note at this point that, although human and probably mitochondrial ribosomes can read the viral copies and generate proteins from it, they do not generate perfect viral proteins. What they do in fact is generating a very long, inactive protein chain, which needs to be broken down by some enzymes known as proteases (Image, 5). This cleavage process yields all the different active viral proteins, and can be carried out by viral proteases which are encoded in the viral genome, but also by human proteases (which do the job for the virus in the first place). The fact that the virus can use human proteases for this purpose is believed to be crucial in the host species jump SARS-CoV2 has recently made (3), and has profound implications in how can we fight coronavirus, as we will cover in our next post.
Once enough viral building blocks are generated, they force the cell to create a vesicle full of viral proteins and RNA copies (Image, 6). They self-assemble inside it and make the human cell release the vesicle full of new viruses. These new viruses will reinitiate the cycle in another cell inside that same body or in a different host (4).
Unlike some other viruses, coronavirus does not actively kill or break the cell down. Instead, all this hijacking event may exhaust the cell and this may lead to its death. In fact, what may happen is that the cell senses this unfavourable situation and commits suicide for the common good in a process called apoptosis so that it cannot serve as a factory for the virus anymore. Some cells of the immune system can also sense abnormal activity in infected cells and can kill them. Too many dead cells, for one reason or the other, is what ultimately causes the fatality.
In our next post we will look at the different therapeutic options we can design based on this deep knowledge of the biology of SARS-CoV2.
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