Scientists find a new way coronaviruses can get into human cells

An international team of researchers has identified an East African bat coronavirus capable of entering human cells. 

Whilst the virus - Cardioderma cor coronavirus (CcCoV) KY43, or CcCoV-KY43 – can bind to a cell receptor found in the human lung, preliminary testing in Kenya suggests it has not spilled over into the local human population.

Rather than work on ‘live’ viruses, the scientists used a public database of known genetic sequences, Genbank, to select and synthesise alphacoronavirus ‘spike’ proteins, including 27 viruses originally isolated in bats, and screened these against a library of coronavirus receptors found in human cells.

Spike proteins protrude from the surface of coronaviruses, including SARS-CoV-2, and bind to specific receptors on human cells, triggering infection.

Funded largely through UK Research and Innovation’s Biotechnology and Biological Sciences Research Council (BBSRC), and Kenya Government’s National Research Fund (NRF), the study brought together UK and Kenyan expertise to show CcCoV-KY43 can bind to the human glycoprotein CEACAM6.

Range of receptors

Writing in Nature, the team from The Pirbright Institute, the University of Cambridge, the KEMRI-Wellcome Trust Research Programme, the University of York and the National Museums of Kenya say their findings show alphacoronaviruses (alphaCovs) can use various receptors to enter human cells.

Dr Dalan Bailey, Group Leader at The Pirbright Institute, said: “Before our study, it was assumed most alphacoronaviruses used just one or two possible receptors to enter their host, and the only difference was which species they could enter. We now know alphaCovs might use a whole variety of additional receptors to get into cells.”

Stephen Graham, Professor of Virus: Host Interactions at the University of Cambridge, said: “Viral spike proteins are keys that fit into locks (host receptors) to open the door and enter a cell. So far, we have identified one alphaCov receptor. The challenge now is to find the others.”

Virus spike

Dr Giulia Gallo, a viral glycoproteins specialist and lead author, said: “Not only did we find the new coronavirus receptor in human cells ahead of any virus spillover into the human population, but the study was performed using just a piece of the virus (the spike) rather than the whole pathogen, negating the need to import a live virus into the UK.”

Professor Gavin J. Wright, University of York, added: “We are delighted that the human receptor discovery platform that we have developed at the University of York identified a new coronavirus receptor. We are confident that this exciting technology will be very useful to identify receptors for other important viruses.”

CcCoV-KY43 is found in heart-nosed bats, or Cardioderma cor, an ecologically important species found mainly in eastern Africa, including eastern Sudan and northern Tanzania.

The researchers say the zoonotic (animal-to-human) and pandemic potential of alphaCoVs has remained relatively unchartered – to date, only two cellular receptors have been characterized for alphaCoVs.

Preparing for spillover

Dr James Nyagwange, KEMRI-Wellcome Trust Research Programme, who was part of the study, said: “Our paper identifies the need for further study in East Africa to better understand the risk from the wider family of viruses that can use this human receptor. This will help humanity prepare for any spillover in the future and to start developing vaccines and antivirals.”

During the study, partners provided specific expertise. Pirbright identified CcCoV-KY43’s ability to infect human cells and confirmed CEACAM6 supports human cell entry. York screened the CcCoV-KY43 spike against a panel of human receptors, identifying CEACAM6 as a ‘hit.’ Pirbright and Cambridge measured how strongly CEACAM6 binds to the spike, and Cambridge solved the spike structure and receptor binding in atomic detail. National Museums of Kenya made initial CcCov detection in bats and mapped it across Kenya, and KEMRI-Wellcome showed where CEACAM6s is expressed in the human body, testing serum from people living in CcCoV areas to see if they might have previously been infected by CcCoV-KY43.

Zoonotic potential

Dr Bailey said: “We would like to apply the same computational technology behind this study to find other potential human pathogens, but also to understand the wider drivers of zoonotic potential.

Professor Graham added: “We hope our findings will help better understand the risk from the family of viruses we identified that can use the human receptor: for example, by mapping the prevalence of the virus in bats and looking to see if it has already spilled over in at-risk populations.”