Notes on the Coronavirus
Image: CDC
Empty restaurants. Schools shut down. Crashing markets. The headlines have been dominated by news about the novel coronavirus. Labeled a pandemic by the World Health Organization, the virus and the disease it causes represent a major health concern that’s having a significant impact on our daily lives and throughout all layers of the global economy.
The news coverage has been a constant stream of stories describing the spread of the virus, various government responses, the huge selloffs in the markets, information about how people can help mitigate the spread of the virus, and other key public health reports. To dig a little deeper, I wanted to learn more about the virus itself, how it’s infecting our bodies and making us sick, and what we’re doing to try to combat it.
Research on the novel coronavirus has been moving quickly, and there are still many unknowns. I’ve tried to use some of the recently published scientific literature to gain a better understanding of what we know about the virus so far. I’ve tried to summarize some of what I found below.
What is the coronavirus?
While you may have heard the virus commonly referred to as the “coronavirus,” the word coronavirus refers to a wider class of viruses that share common features, including a characteristic appearance. As you may have seen in illustrations of the virus, the surface of the viral particles is studded with protein “spikes,” and this results in a crown-like – or corona – appearance when viewed as a cross-section under special microscopes. In humans, these viruses are normally associated with varying levels of respiratory infections, including the common cold.
The novel coronavirus that has dominated the news is officially called SARS-CoV-2 for severe acute respiratory syndrome coronavirus 2 and was discovered in December 2019 as it spread in the city of Wuhan in China. COVID-19, another phrase commonly used in the media, stands for coronavirus disease 2019, the official name for the infectious disease caused by SARS-CoV-2. You can think of the relationship between SARS-CoV-2 and COVID-19 as similar to HIV and AIDS, where infection with the virus (SARS-CoV-2 and HIV) can result in the respective disease (COVID-19 and AIDS).
As its name implies, SARS-CoV-2 is closely related to the virus SARS-CoV, the coronavirus responsible for the SARS outbreak in China in 2002-2003. Both SARS-CoV-2 and SARS-CoV are beta-coronaviruses, a classification that also includes coronaviruses that are responsible for more minor infections, including the common cold. It is believed that bats were the original host species of SARS-CoV-2, which acquired mutations that resulted in its ability to infect other species, including humans.
SARS-CoV-2 and the other beta-coronaviruses are RNA viruses, meaning that they use RNA as the basis for their genome. More specifically, SARS-CoV-2 belongs to a subcategory of RNA viruses called single-stranded RNA viruses. If you think of DNA being a twisted ladder structure, imagine the structure of single-stranded RNA as being only one side of that ladder, as if someone ran a buzz saw right down the middle of each step. The virus uses this half-ladder of RNA for two functions. First, it serves as a template to make more RNA copies. Second, the RNA acts as a blueprint for making new viruses, containing all the information needed to build the necessary components and assemble new virus particles. As described below, the production of these new virus particles occurs using the infected cell’s own construction crews.
How does the virus infect us?
While research is still ongoing to better understand the underlying biology of SARS-CoV-2, people are starting to develop an initial understanding of the virus. SARS-CoV, the related virus responsible for the 2002-2003 SARS outbreak, was found to infect the epithelial cells lining the airways and lungs, the endothelial cells lining blood vessels, and various immune cell types. Both SARS-CoV and SARS-CoV-2 appear to bind to the same surface protein on host cells, and infection with each virus results in similar respiratory symptoms, suggesting that SARS-CoV-2 infects a similar set of host cells.
As discussed above, a distinguishing feature of coronaviruses is their display of viral proteins on their surfaces. The “spike” – or “S” – proteins are used by SARS-CoV-2 to bind to the host cell. These target cells in the host – such as our lung cells – possess a protein on their surface called ACE2. While ACE2 is generally involved in the regulation of blood pressure, it is currently thought that the virus uses it as a gateway into the cell. The virus’s S protein binds to ACE2, triggering the cleavage of the viral S protein by proteins on the host cell. Once cleaved, the S protein fragment possesses a new function: it facilitates the fusion of the viral particle to the host cell, leading to a process that’s similar to how a small soap bubble can merge with a neighboring soap bubble.
During the fusion process, the virus releases its internal contents, including its RNA genome, into the host cell. Once inside the host cell, the viral RNA is essentially indistinguishable from the host cell’s RNA. This means that ribosomes, protein complexes within the cell that use RNA to produce new proteins, unwittingly pick up the viral RNA and generate new viral proteins, the building blocks of new virus particles. The virus hijacks the cell’s normal protein synthesis machinery to produce more viruses. This rapid virus replication can lead to massive host cell death (through apoptosis and possibly pyroptosis, an inflammatory cell death process), leading to tissue damage.
In addition to causing direct tissue damage by infecting cells, the virus is thought to induce a significant inflammatory response from the body’s immune system. The cell death caused by the viral infection appears to result in the production and release of proteins involved in inflammation. These proteins belong to a broad category called cytokines and chemokines, and once they are released into the blood stream, they ramp up the body’s immune response, activating and recruiting immune cells to the site of infection. While this is normally beneficial for fighting infection, this inflammatory response can be hyperactivated. In this situation, the inflammatory proteins induce cells to produce and release additional inflammatory proteins, leading to a self-reinforcing cycle of inflammation. This results in too many inflammatory proteins flowing through the body and too many activated immune cells. When this occurs, you can get a systemic inflammatory condition where there’s a swirling mélange of inflammatory signals and immune cells within the body, a condition that’s aptly called a cytokine storm. Inflammation on this scale can be severely damaging, and cytokine storms can have dire consequences, including significant tissue damage, organ failure, and death. There has been some evidence of cytokine storms occurring in some COVID-19 patients, with some researchers finding elevated blood levels of inflammatory proteins in these patients, as well as damage to organs that wouldn’t normally be closely associated with a respiratory infection.
What treatments are being developed?
Our knowledge of SARS-CoV-2, while limited, provides the basic foundation for how to develop treatments to combat the virus. Multiple companies and countless researchers are working around the clock to identify and develop treatments and vaccines for SARS-CoV-2.
As discussed above, the virus’s S protein plays an instrumental role in its infection process. Because this protein is on the surface of the virus (the spiky projections), it is the predominant target for therapeutic antibodies. Antibodies are Y-shaped proteins produced and released by immune cells during the course of an immune response to infection. Antibodies are designed to specifically target certain molecular patterns, and when they encounter these patterns, the antibodies bind to the target. This binding can result in several outcomes, including neutralization of the target protein’s function. In the case of the viral S protein, neutralizing antibodies would recognize the S protein, bind to it, and prevent it from attaching to the host cell’s ACE2 protein, thereby preventing the infection of that cell.
Moderna, a biotech company in Massachusetts, is collaborating with the National Institute for Allergy and Infectious Disease (NIAID) – a component of the National Institutes of Health (NIH) – on a vaccine that targets SARS-CoV-2’s S protein. Their vaccine, called mRNA-1273, is an RNA vaccine. This means that the vaccine uses RNA that encodes the viral S protein as a way to hopefully build immunity to the virus. When given to a patient, the RNA is taken into cells. Similar to the viral replication process described above, the RNA is used as a blueprint to make the S protein. However, since the RNA doesn’t contain the blueprint for the rest of the virus, no virus particles are produced. Instead, only the S protein is made, which is then secreted by the cells. The S protein is detected by the body’s immune cells as foreign, leading to the normal response against the S protein, including the production of neutralizing antibodies. Because the immune system is now prepped and ready to mount a response to the S protein, when the virus does enter the body, the immune cells can quickly detect the S protein on the virus, activate a quick and appropriate response, and eliminate the virus before serious infection can occur. While this specific vaccination approach to SARS-CoV-2 still has to be proven in clinical trials, the approach represents the underlying theory of how vaccines work. Moderna, as well as other companies working on vaccines for the virus, want to expose to the body to a benign component of the virus so that the body can develop and practice its response and get ready to fight the virus when an infection occurs.
In addition to vaccines, companies and researchers are working on antiviral drugs. Unlike vaccines, which help prepare the body for an infection (proactive), antiviral drugs are designed to directly target the virus itself during an infection (reactive)
One example of an antiviral drug in development for use against SARS-CoV-2 is remdesivir, an experimental compound being developed by Gilead Sciences, a California-based biopharma company. Remdesivir appears to have broad-spectrum antiviral properties against RNA viruses, having been previously tested in humans with Ebola virus, as well as in preclinical models of MERS and SARS, two other conditions caused by coronaviruses. Remdesivir has entered clinical trials for treating SARS-CoV-2. The compound works by inhibiting the viral replication process. More specifically, remdesivir is thought to prevent the virus from properly copying its RNA. Without properly made RNA copies, new virus particles cannot be made. In preclinical studies, remdesivir was shown to reduce the amount of virus particles present in key tissues.
To complement the work being done on vaccines and antiviral compounds, researchers are also testing the potential of drugs that mitigate the effects of the cytokine storm. As an example, scientists in China have tried repurposing an FDA-approved rheumatoid arthritis drug to combat the effects of the cytokine storm associated with COVID-19. The drug, called tocilizumab and developed by the pharma company Roche, is an anti-inflammatory drug that inhibits a key component of the cytokine storm, a cytokine called IL-6. In the context of a cytokines storm, this protein helps ramp up the immune response, contributing to increased inflammatory damage. Tocilizumab is a neutralizing antibody that targets the receptor for IL-6. When tocilizumab binds to the IL-6 receptor, it prevents IL-6 from binding and activating its receptor, thereby neutralizing the signaling induced by IL-6 and helping to break the inflammatory cycle. By targeting a damaging symptom of COVID-19, researchers hope to improve patient outcomes and produce a therapy that could complement the other avenues of drug development for SARS-CoV-19.
While this can feel like a scary time that’s full of uncertainties and challenges, every new piece of information helps transform unknowns into knowns, slowly lifting the veil of ignorance and fear. This can be comforting, since the more you know, the less scary things can feel. I am reassured by the fact that there are so many researchers and clinicians working to identify and develop treatments to fight this virus. As the world comes together to fight this pandemic, I’m sure that new knowledge and solutions are on the horizon.
Thanks to Qiagen and Todd Festerling for sponsoring the blog.