New research shows that the bat virus’s closest relatives of the human Middle East Respiratory Syndrome (MERS) coronavirus efficiently bind to bat ACE2 receptors as an entry point into these cells. These receptors have some similarities to the ACE2 receptors on human cells.
However, at present this coronavirus, called NeoCoV, and a similar virus, PDF-2180, only weakly bind to human ACE2 cell receptors as a point of entry into cells. They are also not known to cause disease outbreaks in people.
“To date,” the scientists reporting on this latest research noted, “there is no evidence that NeoCoV and PDF-2180 can infect mammals other than bats.
Surprisingly, the MERS coronavirus, like some other related and well-characterized merbecoviruses, uses an entirely different cellular receptor called DPP4 (dipeptidyl peptidase-4).
Human ACE2, an angiotensin-converting enzyme receptor, is the main cellular entry receptor for infections in people with SARS-CoV-2, the coronavirus that causes COVID-19. It is also the human cell receptor for SARS-CoV-1, the cause of Severe Acute Respiratory Syndrome, identified in 2003 after an outbreak of pneumonia that was later confirmed to have been species-hopping.
In general, many other sarbecoviruses, an alphacoronavirus (setracovirus), and a group of merbecoviruses share the ability to bind to ACE2 in the cells of certain animals. The convergent evolution that led to very different coronaviruses using ACE2 as entry receptors remains unclear.
Cryoelectron microscopy analysis revealed that NeoCoV has a distinct way of binding to the bat ACE2 receptor, compared to the other coronaviruses known to use that receptor.
The findings of this research, carried out by an international team of scientists, appear in the December 7, Nature. The article’s first and corresponding authors are David Veesler, an associate professor of biochemistry at the University of Washington School of Medicine in Seattle and a Howard Hughes Medical Institute Investigator; Xiangxi Wang from the Institute of Biophysics of the Chinese Academy of Sciences in Beijing and Huan Yan from the Wuhan University College of Life Sciences.
Finding that ACE2 is the host cell receptor for NeoCoV and PDF-2180, which are closely related to the deadly human pathogen MERS-CoV, was totally unexpected and opens up new avenues to prepare for potential future zoonotic transmission of these viruses, according to the researchers in this study. This information is critical for establishing a watch list of animal virus families that pose a risk of emerging as zoonotic diseases in people.
The lack of knowledge about which cell receptors bat coronaviruses use, the researchers explained, limits scientific understanding of their cell entry strategies and of the propensity of the virus for cross-species transmission.
Looking at the intricacies of how coronaviruses use cell receptors, the researchers noted in their paper, highlights the importance of additional research and surveillance on these viruses to stay ahead and prepare for future outbreaks.
The researchers in this current study also sought to collect data that could provide clues to the origin of MERS-CoV. Their results support previous hypotheses that MERS-CoV may have arisen after a recombination event between a virus that was NeoCoV-like and a virus that preferred the DPP4 cellular receptor.
While the history of this event has not been confirmed, scientists surmised that such genetic reassortment in viruses may occur when a host animal is co-infected with different coronaviruses. In this way, a new coronavirus may emerge, using a different cellular receptor with a possible expansion of the host range.
For MERS-CoV, the scientists noted that it remains unclear whether such an event might have occurred in bats, camels, or other animals, or when the switch to a new animal (or human) host might have occurred.
The two viruses, NeoCoV and PDF-2180, prefer ACE2 cell receptors in vesper bats, part of the Vespertilionidae species. Most merbecoviruses are found in that species. This is a remarkably diverse and widely dispersed species of bat.
While NeoCoV does not have a strong affinity for the ACE2 receptor on human cells, the scientists noted that NeoCoV might undergo adaptive changes that would allow it to enter human cells more easily. Extensive mutations in key cell junction regions of the COVID-19 (SARS-CoV-2) virus, particularly in the Omicron variant, indicate that other coronaviruses may have the as yet unrealized ability to adapt through mutations.
On the other hand, the spread of viruses from one animal species to another is a complicated transition that involves not only recognizing a cellular receptor in the species to which it jumped, but also subverting host immune responses, timing of contact, conditions suitable for the virus to replicate. , and many other factors.
The researchers also noted that MERS-CoV antibodies and antibodies generated by current COVID-19 vaccines do not adequately neutralize NeoCoV and PDF 2180. However, their results showed that broadly neutralizing antibodies that target evolutionarily conserved regions of NeoCoV and PDF-2180 does inhibit the entry of these viruses into the cell. They suggest that these broader-acting antibodies should be considered for preparation against human transmission from these viruses.
Washington University School of Medicine/UW Medicine
Xiong, Q. et al. (2022) Close relatives of MERS-CoV in bats use ACE2 as their functional receptors. Nature. doi.org/10.1038/s41586-022-05513-3.