By Yidan Gao, Edited by Edward Chen
Coronaviruses have been around for a long period of time, accompanying mankind since the mid-1960s. Some of its family members are now big names in the news, while others are not. Similar to all species, viruses undergo natural selection—the process by which organisms better adapt to their environments in order to survive and produce more offspring. In the context of a virus, it undergoes evolution to become better at infecting its host and to produce more of itself via replication. In this blog, I touch on how “smart” SARS-CoV-2 can be. There are some nitty-gritty biological terms, but they will be broken down into very casual definitions for you to understand.
The very first aspect of coronavirus “intellect” comes from the fact that SARS-CoV-2 can survive in different hosts. In fact, viruses in general are able to accommodate different hosts and species. A typical example is the Schmallenberg virus associated with disease in ruminants. It was originally spread by sheep, goats and cows, but this virus has now burned out and is no longer spread within the animal population. This proliferation of a virus across a wide range of species is a process in which the virus develops a stable relationship with the new host; the interactions between virus and host vary depending on the specific species. A very interesting study published in The Lancet looked at different animal hosts that SARS-CoV-2 might infect. Using nasal swabs, the researchers infected fruit bats, ferrets, pigs, and chickens with the same amount of the SARS-CoV-2 virus, then assessed how different species reacted to their infection. While pigs and chickens were unsusceptible to SARS-CoV-2, fruit bats were the most susceptible to infection, with viral antigen detected through fecal samples. Viral replication was observed in ferrets, but no clinical symptoms were observed. We can see from these results that SARS-CoV-2 has adapted ways to proliferate in different hosts, ranging from wild animals in the night sky to cuddly animals in the pet store. In addition, the symptoms of infection between different species can range from none to severe.
Let us discuss some of the virology of SARS-CoV-2. Many aspects of this virus’s life cycle are unique, including its way of entry and its replication machinery. The initial step of infection starts when the spike protein of SARS-CoV-2 ‘sees’ ACE2, its receptor that is expressed in airway epithelial cells. The entry process is similar to a Jack-in-the-box. There are two components of the viral spike protein: the receptor binding domain (the lid) and the fusion peptide (the Jack). The lid region interacts with the ACE2 protein on a host cell. This interaction causes a conformational change of the viral protein in such a way that the lid is opened, allowing the fusion peptide to enter the cell through the opened pore. Recently, D614G, one of the key mutations of SARS-CoV-2, has been brought to the public’s attention. This mutation occurs within the fusion machinery portion of the virus, and allows it to be injected more easily into the host cell.
Another interesting aspect of SARS-CoV-2 comes down to its replication machinery. A double-stranded RNA (dsRNA) virus like the coronavirus uses a protein called RNA polymerase to replicate its genetic material. Generally, we want our replication machinery to be as flawless as possible to avoid deleterious (or damaging) mutations. This is why the RNA polymerase in our cells has a proof-reading ability, so that an error can be detected and fixed. In contrast, most of the viruses do not have this proof-reading ability in their polymerases, which makes them prone to mutations. Interestingly though, SARS-CoV-2 has this proof-reading ability, similar to humans. This feature then allows them to encode more proteins that are involved in sophisticated interactions with the host.
The next important question for SARS-CoV-2 is how they evade the host protective mechanism. Essentially, SARS-CoV-2 needs to silently convert the host into a viral factory without waking up the host’s antiviral response. There are two strategies they implement. The first strategy is to perform viral functions in an isolated compartment within the cell. Our cells are very sensitive to dsRNA, because dsRNA is not usually found in the cytosol of our cells under normal conditions, and nucleases in our cytosol degrade dsRNA if it is detected. This is a nightmare for SARS-CoV-2 because it needs to generate dsRNA as its genetic material. To overcome this obstacle, SARS-CoV-2 remodels the inside of the cells they infect by tearing off a part of the membrane from the endoplasmic reticulum (an organelle in our cells) and creating double membrane vesicles. They can then replicate their genome within these isolated vesicles and avoid sensor proteins that would otherwise destroy their dsRNA.
The second strategy SARS-CoV-2 uses to avoid detection is to change the expression of host genes. As one can imagine, a cell has a limit on the amount of work that it can do in a given time frame. When a virus infects a cell, the virus needs to find a way to reallocate part of the host cell’s efforts and resources to furthering the virus’s own metabolism and survival. Viruses do not have a way to convert their genetic material (RNA or DNA) into proteins on their own. Luckily for the virus, host cells have ribosomes, or protein factories that convert RNA into proteins. SARS-CoV-2 hijacks human ribosomes by shunting protein expression to its own replication mechanism. More specifically, it encodes a protein, Nsp1, which acts like a fork. Nsp1 inserts into the ribosome compartment and prevents the entry of the host RNA. In this case, the host’s gene expression of some immune function modulators (proteins that can detect and fight viruses) is halted. SARS-CoV-2 thus succeeds in both protecting itself and making its necessary proteins.
It is fascinating to learn about how “smart” these viruses are by examining the mechanisms that they develop in order to better survive in their host. There are many more interesting aspects of the coronavirus that are still in the process of being explored. As the Chinese proverb goes, “Know the enemy, know yourself and in every battle, you will be victorious.” Understanding the virus’s mechanism is an important step in designing vaccines or medical interventions that can target different, yet unique viral proteins.
Results from ongoing research and the current understanding of COVID-19 are constantly evolving. This post contains information that was last updated on October 13, 2020.
Edward Chen is a master's student studying immunology. He's also the national president of Students vs. Pandemics. @EdwrdChen
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