Coronavirus SARS-CoV-2: What virologists have yet to find out

The emergence of SARS-CoV-2 and its spread across the planet is an unprecedented opportunity for virologists to witness the development of a new coronavirus “live”. Equipped with better-performing tools than ever to analyze the causes and consequences, what have they learned over the past year?

Anne Goffard, coronavirus specialist, summarizes the current state of knowledge.

The Conversation: SARS-CoV-2 conquered the planet in early 2020, spawning the Covid-19 pandemic. How has knowledge about this virus progressed?

Anne Goffard: Before the epidemic began, there was no serological test for coronaviruses. There was no vaccine, no treatment, and little was known about how to manage patients. In one year, specific RT-PCR diagnostic tools for SARS-CoV-2 have been developed, serological tests have been developed, and several vaccines are now available. These advances, which should make it possible to control the pandemic, were obtained quickly, even if this period of one year may seem long.

Admittedly, there is not yet a specific treatment for SARS-CoV-2, but we have learned a lot, and quickly, on the clinical aspects. The management of patients has evolved enormously compared to what it was a year ago, when we were less familiar with the disease. We now know when to use corticosteroids such as dexamethasone, how to treat severe forms by resorting to less aggressive treatments than in the early stages, etc. Deaths have decreased as a result.

TC: On the other hand, we have made less progress in understanding the virus itself and its way of interacting with the immune system ...

AG: Effectively. The answers will arrive gradually, in a year, two years ... This is research that requires a lot of time, because it is about fundamental virology.

We must first be able to reproduce in the laboratory the multiplication of SARS-CoV-2, on cells in culture. The tools existed, but they had to be adapted to this new coronavirus, which took time. Once these methods have been developed, the various specialists can begin to carry out their research: the immunologists will seek to identify the pathways of immunity that the virus activates or inactivates, the fundamental virologists cause the production of modified viral proteins in order to study how they interact with different cellular compounds such as the ACE2 receptor, the "lock" used by SARS-CoV-2 to open a passage allowing it to enter cells ...

Once the first data is obtained, it is necessary to validate it, compare it with the data of other research groups… Some work has already generated results. For example, the Spike glycoprotein has been characterized very quickly (this protein, present in numerous copies on the surface of the virus, interacts with the ACE2 cell receptor and allows SARS-CoV-2 to enter cells). Why ? Because we knew, from our experience with other viruses, that it is the protein that produces the strongest reactions of the immune system. It is therefore important for the development of vaccines. To be able to launch research on this subject, it was essential to know a certain number of the characteristics of this protein.

TC: What are the next steps?

AG: The results which will be the most interesting are the results on the characterization of the viral enzymes, which will be the polymerase and the proteases of the virus. The first allows it to copy its genetic material, an essential step for its multiplication in infected cells. The second are kinds of "scissors" that are used to resize the proteins that it makes these cells produce, such as those that constitute its viral capsid (the shell that protects the genetic material of the virus). This step is essential to make them usable.

Polymerase and protease are very important targets for antiviral drugs. Anti-HIV treatments contain anti-proteases and anti-reverse transcriptases (the name of HIV polymerase). To develop effective antivirals, it is important to be familiar with these enzymes. You must first be able to understand the three-dimensional structure, so that chemists who design drugs can create molecules that will “stick” to the important parts of these enzymes, preventing them from functioning. .

It is not simple, because, in order to be able to study them, it is necessary to produce large quantities of these enzymes, with a very high degree of purity (in order not to disturb the very precise analyzes which will be carried out subsequently).

Another expected result are those of research on "Universal vaccines". The idea would be to successfully develop vaccines that trigger the production of broadly neutralizing antibodies (bNAb). These antibodies would target protein motifs conserved on the surface of related viruses, which would make them effective against the various variants in circulation. Work has been carried out for several years on HIV in particular.

Finally, people who study viral epidemiology expect to see variants more suited to humans to emerge. Indeed, we know that when a virus infects a new host, it takes a certain time to adapt to it, but generally ends up doing so. It then loses in virulence. These mechanisms are well known for the influenza virus: after a year or two, the viruses responsible for influenza pandemics subside and become epidemic influenza viruses, returning every winter.

So far, no such attenuation has yet been observed for the coronavirus. This is not necessarily surprising, because unlike the influenza virus, coronaviruses have a mechanism to correct errors that can occur when they copy their genetic material. They therefore evolve less quickly: the emergence of variants was notably longer than in the case of influenza. In their case, this is the first time we have witnessed this process, so we do not know how long it takes.

TC: The origins of the virus also remain to be elucidated?

AG: Yes. While we are certain that the virus originated in bats, we still do not know which intermediate host (or intermediate hosts) allowed it to pass from this animal to humans. . It was thought at one time that it was the pangolin, but in the end it turned out to be unlikely.

The identification of intermediate hosts is important because it makes it possible to understand the mechanisms that led to the emergence of the virus in humans, and therefore to propose measures to avoid new emergence. These are very long investigations, which require the mobilization of naturalists capable of identifying the Asian species that may have been involved, of collecting samples from the wild fauna, of analyzing them, etc. It also takes a lot of time.

Anne Goffard, Doctor, University Professor - Hospital Practitioner, University of Lille

This article is republished from The Conversation under Creative Commons license. Read theoriginal article.

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