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Reaction to the discovery of a new sarbecovirus in Russian bats resistant to SARS-CoV-2 vaccines

A sarbecovirus distantly related to SARS-CoV-2 and found in horseshoe bats in Russia is able to enter human cells using the ACE2 receptor, according to research published in PLOS Pathogens. 

22/09/2022 - 20:00 CEST
Expert reactions

Juan Echevarría - murciélagos

Juan Echevarría

Scientific researcher at the Reference and Research Laboratory for Immunopreventable Viral Diseases of the National Microbiology Centre - Carlos III Health Institute

Science Media Centre Spain

Human beings, like any other living being, have their own catalogue of viruses that infect us, causing disease or not, and which have been transmitted to us by other species at some point in the past. In recent decades we have witnessed the AIDS pandemic, caused by the Human Immunodeficiency Virus (HIV), which was transmitted to us by the chimpanzee and the gorilla, or the covid-19 pandemic, the origin of which is still unknown. In addition, we have seen other outbreaks of emerging diseases that we have been able to control and which have not led to pandemics, such as SARS, MERS, Ebola and Marburg virus disease.

The first step in the infection of a cell by a virus is the interaction between a region of a protein in the virus that we call the "receptor-binding domain" and a region on the cell surface that we call the "receptor". This binding is very specific and is often referred to as the simile of the key and the lock to explain it in a straightforward way. This specificity is largely responsible for the fact that each virus can only infect one species or a small catalogue of species. On rare occasions, this biological barrier can be overcome and what is known as a "species jump" occurs, expanding the virus catalogue of the host species by one element. 

SARS-CoV-2, the virus that causes covid-19, enters cells through a receptor called ACE2 that is widespread among animals, although its sequence and structure varies between species. This restricts the ability of SARS-CoV-2 to infect only a few species and, in particular, humans. Although we do not know which animal species transmitted SARS-CoV-2 to us, we know that bats harbour a variety of related viruses that, together with SARS-Cov-1, SARS-CoV-2 and a few viruses from other mammals, such as the pangolin, form the sarbecovirus group, within the coronavirus family. It is thought that these bat sarbecoviruses may be the ancestors of SARS-Cov-1 and 2, although the evolutionary process that led to them is unknown. 

It should be stressed that neither SARS-CoV-1, nor SARS-CoV-2, nor any other coronavirus capable of infecting us has ever been detected in bats. On the other hand, sarbecoviruses (all coronaviruses, in fact), are characterised by the ability to exchange genetic fragments easily (recombination), giving rise to new viruses that combine characteristics of their progenitors. Therefore, there is a hypothetical fear that a new pandemic sarbecovirus could be generated through this mechanism, which is totally unknown to our immune system, but which could infect us, causing an epidemic. 

Given the diversity and frequency of sarbecoviruses in bats, particularly in horseshoe bats (Rhinolophus), an intensive search for sarbecoviruses in these animals has been underway for some years. In this context, two years ago, two new sarbecoviruses were described in Russian horseshoe bats that were quite similar to others from Bulgaria and Kenya and somewhat more distant from those from East Asia, including SARS-CoV-1 and SARS-CoV-2. In the present work, the authors study the interaction between the receptor-binding domain of these two new sarbecoviruses and the human ACE2 receptor. Since they have not been able to grow the virus in cells, they resort to the construction of chimeric viruses (pseudoviruses), expressing the spicule (or its receptor-binding domain) of these two new sarbecoviruses in an unrelated virus capable of growing in cell cultures. Using this experimental model, they show that the receptor-binding domain of these two viruses is able to interact with human ACE2. They also show that these chimeric viruses are not neutralised by antibodies to SARS-CoV-2. 

The article concludes by highlighting the need to obtain broad-spectrum sarbecovirus vaccines that can protect against any new ACE2-dependent sarbecovirus that may emerge in the future by the mechanisms described above. It should be noted that this is not the case for these two viruses, nor for any of the other non-human sarbecoviruses known to date, which are not capable of infecting human cells. Recall that binding of the virus to the cell surface receptor is only the first step for infection to occur, which requires many additional interactions that neither these two new viruses, nor any other known bat sarbecovirus, are able to perform, as they lack the necessary elements to do so.

It is therefore wrong to say that two new bat coronaviruses capable of infecting human cells have been discovered. Scientific work such as this puts us on the right track to prevent future pandemics caused by this group of viruses. Thus, we must avoid generating unnecessary and harmful fear. 

The author has not responded to our request to declare conflicts of interest

María Iglesias - murciélagos sarbecovirus EN

María Iglesias-Caballero

Virologist at the Reference Laboratory for Influenza and Respiratory Viruses of the National Microbiology Centre - Carlos III Health Institute

Science Media Centre Spain

Research on potential zoonoses is part of the "One Health" strategy, can provide knowledge on the biology of the virus and allows us to monitor the potential risks we face. The occurrence of sarbecovirus in different bat populations across the globe is well known, but it is no less important to study it.

This work, with a good sampling and sequencing methodology previously published, characterises two coronaviruses structurally and antigenically. Its relevance is to show the potential ability, especially of one of the viruses, to infect human cells and the impact it may have on population immunity in the case of species jumping of these viruses.

It also opens up an interesting field of work, which is already underway on the new SARS-CoV-2 variants and their relationship with human receptors, in which other routes of virus entry and the use of other proteases for processing the spicule are assessed. Potential findings of new receptors in bats may help to improve our understanding of cell entry in humans.

As the only weak point, and understanding the difficulty that this entails, I would stress that these results must be taken into account, but handled with caution, as they are carried out with pseudoviruses and not complete viruses. Cultivating bat viruses can be very difficult, but it would have been a perfect cherry on top of this work, which indicates that we must continue to monitor the viruses we find in bats because information always allows us to make better decisions.

The author has not responded to our request to declare conflicts of interest

Candelas - murciélago

Fernando González Candelas

Professor of Genetics at the University of Valencia and researcher at FISABIO, specialist in epidemiology and evolution of viruses and bacteria

Science Media Centre Spain

This work builds on the previous discovery of novel coronaviruses in horseshoe bats from southern Russia. Many species of bats in this family harbour different coronaviruses and are the best candidates to represent the original host of SARS-CoV-2 before its jump to humans. Therefore, the question they set out to answer is whether these new viruses could infect individuals of our species.  

To this end, they have carried out various tests with cell cultures and virus proteins, specifically the spicule and its cellular receptor-binding portion, to check whether the virus protein is capable of recognising and binding to different receptors present in human cells. The answer is that one of these viruses, the so-called Khosta2, is able to do so and, moreover, it recognises the same cellular receptor mainly used by SARS-CoV-2 to infect our cells, ACE2 (angiotensin-converting enzyme-2). 

The result is not completely novel because other coronaviruses have also shown this capacity and some of them have been analysed in this work. The biggest surprise is that this ability is present in a virus that is not closely related to SARS-CoV-2, but belongs to a different lineage. The study highlights the great plasticity in the cellular receptor binding capacity of coronaviruses, including some that are related to human pathogens, such as SARS-CoV-1, and others that infect us but do not cause severe symptoms, such as HCoV-229E. 

The discovery that SARS-CoV-2-like coronaviruses isolated from bats outside Southeast Asia could infect humans - it should be recalled that the tests have been conducted under laboratory conditions - represents a further wake-up call for the need to keep a close eye on new emerging pathogens even in areas of the planet that have not hitherto been considered to harbour relevant threats. 

The author has not responded to our request to declare conflicts of interest
An ACE2 dependent Sarbecovirus in Russian bats is resistant to SARS-CoV-2 vaccines
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PLoS Pathogens
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