Prof Jonathan Ball, Deputy Vice-Chancellor and Professor of Molecular Virology, Liverpool School of Tropical Medicine, said:
“This is excellent work and gives us further insights into the wealth of coronaviruses that could make a successful jump into humans. And this probably represents the proverbial tip of the iceberg. The screening approach was designed to take a deep dive into alphacoronavirus diversity, whilst at the same time yield a workable number of candidate spike proteins – the surface protein that allows the virus to gain access into the host cell – to test for their ability to enter into human cells. Using this approach, they whittled down the number of different bat-virus proteins to test from thousands to forty, and within this small subset they found one capable of human cell entry. It is possible that more of the other bat viruses are able to enter humans cells.
“The fact that there is little evidence of exposure of human population living in the vicinity of the bats is reassuring – we know that successful entry into cells is just the first step in successful human infection and, importantly, onward human to human transmission, so maybe these viruses aren’t yet able to successfully make the jump. But who knows for sure, and understanding the potential for these and other coronaviruses to spillover from their animal reservoirs into humans is important and timely work.
“The study is great quality – but likely misses viruses with potential to spill over (as they use a reductionist approach) but equally we don’t know if those hits have the full repertoire to be able to properly infect then transmit in humans.”
Dr Jonathan Stoye, Senior Group Leader and Head of the Retrovirus-Host Interactions Laboratory, Francis Crick Institute, said:
“There are multiple cases of human pandemics resulting from zoonotic transfer of animal pathogens, AIDS and COVID being just two examples. It would therefore be desirable to identify infectious agents with pathogenic potential that are present in animals without at the same time performing studies that increase the risk of human infection. This insightful and robust study describes one approach to this problem, using computational methods combined with pseudotyped, non- infectious, viruses. It identifies a coronavirus from Kenyan bats called CcCoV-KY43 with a spike protein capable of productive interaction with a receptor protein on human cells. Such an interaction is key to virus infection, in its absence the cell remains completely resistant. Thus, this study definitively identifies one more virus which may be capable of infecting humans without prolonged replication in intermediate hosts. However, the extent of any danger from this particular virus, if any, remains unclear since serological studies of local populations provide no evidence for infection. Moreover, we know that although receptor compatibility is essential for infection there are multiple other cellular barriers to growth of any virus. Perhaps development of alternative pseudotype systems to test other phases of the viral replication cycle might be informative for evaluating risks posed by this virus. Finally it is worth noting that the present study is limited to forty coronaviruses; it remains uncertain whether this sample is truly representative of the different coronaviruses present among the huge multitude of bat species found on the African continent.”
Prof Wendy Barclay, Regius Professor of Infectious Disease and Chair in Influenza Virology, Imperial College London, said:
“This multidisciplinary team have made an important discovery, finding a new type of receptor that coronaviruses present in bats could use to enter human cells. Thankfully the scientists did not find that people in the East African area where the bats are found have yet been infected but the potential for the virus to jump is there.
“What is very nice about this elegant work is that all the discoveries were made without the need to work with any dangerous viruses; the scientists used a state of the art approach taking sequences derived from the original bat samples in Kenya to recreate surrogates that mimic the virus but are not infectious to humans. The use of a platform to scan huge range of potential human receptors is also a big advance here.
“Nonetheless we do need to acknowledge that further understanding of the potential of these viruses to cause human outbreaks and transmit between people would require working with the whole virus. Indeed, receptor binding is the first step in the pathway for an animal virus to infect humans: it is necessary but not sufficient so we don’t yet know whether the absence of human infections with this virus is due to other as yet undefined barriers to its ability to infect us, or simply due to low exposure.”
Prof Ed Hutchinson, Professor of Molecular and Cellular Virology, MRC-University of Glasgow Centre for Virus Research, University of Glasgow, said:
“The COVID pandemic highlighted the risks of animal viruses adapting to grow well in humans. However, there are an enormous number of animal viruses out there, and in practice most of them don’t cause pandemics because they can’t infect human cells. To infect a cell, the first thing a virus has to do is to bind to an ‘entry receptor’ - a specific molecule on the cell’s surface. When a virus infects a new host species it has a problem: the cells will be coated with different molecules from the ones the virus is used to, and the virus is unlikely to be able to get in. This is not the only factor controlling an infection, but if we understood this well enough we would be able to make risk assessments of which viruses can get a ‘foot in the door’ when infecting humans. In practice, for most viruses we don’t know what the entry receptors are, let alone if human cells carry them.
“This new study set out to solve this for the alphacoronaviruses. This large group of viruses includes one of the common cold viruses that infect humans and many viruses of non-human animals, particularly bats. It is distinct from, but related to, the betacoronavirus family, which includes SARS-CoV-2. All coronaviruses bind to entry receptors using ‘spike’ proteins that stick out from their surfaces. To identify the entry receptors for these viruses, the authors synthesised the spike proteins for all known members of the alphacoronaviruses and looked for ones that could bind human entry receptors. Importantly, none of the work in this study used infectious coronaviruses, just components of them, so the study itself poses no risk.
“The work identified a human protein that could function as an entry receptor for some of these non-human coronaviruses. This highlights that the alphacoronaviruses could include animal viruses that have the potential to infect humans. It is an impressive example of our growing ability to screen for viruses which have a risk of causing pandemics, based on genome sequencing, high-throughput screening methods and AI structure prediction.
“However, surveys of people who encounter the bats carrying these viruses did not find any evidence of human infection. This is also important - it is a reminder that there are multiple barriers that viruses need to cross in order to start a new pandemic in humans, and we will need to consider all of them to understand and manage risk - not just receptor binding, but also the virus’ ability to replicate in human cells, evade human immune responses and to actually encounter human beings to infect in the first place.
“This study is a powerful proof of concept. Although it focusses on only one aspect of the complex process of viral infection and replication (the interactions between molecules at the cell surface) it is well controlled and uses cutting-edge approaches to carry out studies on many viruses at once that would previously have been very time consuming to do with even a single virus. It models the sort of risk assessment which it would now be desirable to apply more widely to other virus families that could pose a pandemic risk to humans.”
Prof Aris Katzourakis, Professor of Evolution and Genomics, University of Oxford, said:
“This is high quality, robust work. One limitation is that, although we know these viruses can enter human cells, we can never be sure exactly how the live virus will behave if it makes the jump to humans, for example with respect to interacting with innate immunity. Nevertheless the risk highlighted is important.
“This study represents an important advance in pandemic preparedness. Global surveillance for coronaviruses has understandably focussed on betacoronaviruses, the lineage that includes SARS-CoV-2, and their usage of human receptors like ACE2. This work demonstrates these bat alphacoronaviruses can exploit an entirely different receptor to enter human cells. This both highlights an important newly-identified entrance point for these viruses and highlights how diverse such receptor usage can be.
“This work is important in flagging that these viruses could overcome one of the key hurdles that could lead to a future crossover event. Such possible crossover events could be the first step in future epidemics or even pandemics – though we are not at that stage yet and it isn’t inevitable. This is a key early warning, and the authors have elegantly combined sequence analysis, epidemiology and structural work, with safe pseudovirus assays to demonstrate this. At the same time, of course, receptor binding is only the first step in viral emergence, which requires a confluence of events to occur. We don’t yet know if these viruses would successfully replicate in humans should a spillover occur, but we now have been forewarned that they can cross the first important barrier.”
Prof Benjamin Neuman, Professor of Biology, Texas A&M University, said:
“This appears to be an excellent study, well-written, drawing reasonable conclusions from strong data.
“Coronavirus KY43 was one of many orphan coronaviruses, known from its genes and probable bat host, but never studied it in a lab or associated with a disease.
“The viruses from Africa and Asia that this study shows are able to use CEACAM6 belong to the genus Alphacoronavirus, subgenus Decacovirus, and are most closely related to the species Alphacoronavirus ferrumequini, itself another of many orphan coronavirus.
“This paper wraps up four studies that could each have made an important paper - a new coronavirus receptor (CEACAM proteins are found on the cell surface, and CEACAM1 was known to be an entry receptor used by mouse coronaviruses, but CEACAM6 has not been reported to be the main entry receptor for any coronavirus before), a broad survey of orphan coronaviruses, a structure of the point of contact between virus and host, and study of the prevalence of the virus among people living near where it was isolated.
“People who study human viruses usually have to play catch-up, responding to new outbreaks as they spread - this is a rare case, where a virus with a toolkit that would, at least in theory, make it possible to spread in people was spotted before it caused any harm, as far as we can tell.
“This virus is able to bind and potentially enter human cells, but to spread between people the virus would need to evade the immune system and a host of other intracellular factors. At present there is no evidence of immune evasion by these viruses. And we don’t know what sort of disease it might cause, if any. Showing that the virus could enter human cells is important, but to understand the potential for disease, we would need to know more about how the immune system respond to infection, and that was not studied.
“This study shines a light on another of the depressingly many viruses lurking just outside public consciousness, awaiting a chance encounter that could open the door to spreading in people. Think of KY43 as one of a million viruses, poised for a one-in-a-million chance to make the leap from bats to people. History tells us that one virus will break through, but which, we cannot guess. When or if KY43 spreads in people, we can only guess - so for now, science does its job, studying and preparing, building a bulwark of knowledge against an uncertain future.”
Declared interests
Prof Jonathan Ball: “No CoI.”
Dr Jonathan Stoye: “I have no potential conflicts of interest.”
Prof Wendy Barclay: “I declare no conflicts.”
Prof Ed Hutchinson: “Ed Hutchinson is the Professor of Molecular and Cellular Virology at the MRC-University of Glasgow Centre for Virus Research.
Disclosures: I have received honoraria for work in a steering group of the Centre for Open Science (Open Practices in Influenza Research; 2021-2022) and on an advisory board for Seqirus (2022). I have unpaid positions on the board of the European Scientific Working group on Influenza and other respiratory viruses (ESWI) and as a scientific adviser to PinPoint Medical. I have received grant funding from the Wellcome Trust and UKRI, including for research on H5N1 influenza.”
Prof Aris Katzourakis: “No competing interests.”
Prof Benjamin Neuman: “I do not, to my knowledge, have any competing interests or conflicts of interest to disclose in relation to the present study. I work in new coronavirus discovery, and coronavirus taxonomy as part of the ICTV, but I am not directly associated with this study in any way.” | 
