Covid-19 China: Researchers identified NeoCoV strain – potential bio-safety threat

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Researchers from Institute for Vaccine Research and Modern Virology Research Center at the  College of Life Sciences, Wuhan University -China are urgently warning that a new deadly coronavirus that is already affecting bats might make a cross-over to humans anytime soon as it has been found to have evolved to be able to bind to human ACE2 receptors. The strain is a type of MERS-Coronavirus.

The study team say that this new strain of coronavirus could very easily make the jump from animals to humans and are warning that the identified NeoCoV strain is a potential “bio-safety threat.”

The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.01.24.477490v1

Coronaviruses (CoVs) are a large family of enveloped positive-strand RNA viruses classified into four genera: Alpha-, Beta-, Gamma- and Delta-CoV. Generally, Alpha and Beta-CoV can infect mammals such as bats and humans, while Gamma- and Delta-CoV mainly infect birds, occasionally mammals6-8.

It is thought that the origins of most coronaviruses infecting humans can be traced back to their close  relatives  in bats, the most important animal reservoir of mammalian coronaviruses   9,10. Coronaviruses are well recognized for their recombination and host-jumping ability, which has led to the three major outbreaks in the past two decades caused by SARS-CoV, MERS-CoV, and the most recent SARS-CoV-2, respectively11-14.

MERS-CoV belongs to the linage C of Beta-CoV (Merbecoviruses), which poses a great threat considering its high case-fatality rate of approximately 35%15. Merbecoviruses have also been found

in several animal species, including camels, hedgehogs, and bats. Although camels are confirmed intermediate hosts of the MERS-CoV, bats, especially species in the family of Vespertilionidae, are widely considered to be the evolutionary source of MERS-CoV or its immediate ancestor16.

Specific receptor recognition of coronaviruses is usually determined by the receptor-binding domains (RBDs) on the carboxyl-terminus of the S1 subunit (S1-CTD) of the spike proteins17. Among the four well-characterized coronavirus receptors, three are S1-CTD binding ectopeptidases, including ACE2, DPP4, and aminopeptidase N (APN)1,18,19. By contrast, the fourth receptor, antigen-related cell adhesion molecule 1(CEACAM1a), interacts with the amino-terminal domain (NTD) of the spike S1 subunit of the murine hepatitis virus20,21.

Interestingly, the same receptor can be shared by distantly related coronaviruses with structurally distinct RBDs. For example, the NL63-CoV (an alpha-CoV) uses ACE2 as an entry receptor widely used by many sarbecoviruses (beta-CoV linage B)22. A similar phenotype of cross-genera receptor usage has also been found in APN, which is shared by many alpha-CoVs and a delta-CoV (PDCoV)7. In comparison, DPP4 usage has only been found in merbecoviruses (beta-CoV linage C) such as HKU4, HKU25, and related strains2-4.

Intriguingly, many other merbecoviruses do not use DPP4 for entry and their receptor usage remains elusive, such as bat coronaviruses NeoCoV, PDF-2180-CoV, HKU5-CoV, and hedgehog coronaviruses EriCoV-HKU315,23-25. Among them, the NeoCoV, infecting Neoromicia capensis in South Africa, represents a bat merbecovirus that happens to be the closest relative of MERS-CoV (85% identity at the whole genome level)26,27.

PDF-2180-CoV, another coronavirus most closely related to NeoCoV, infects Pipisrellus hesperidus native to Southwest Uganda23,28. Indeed, NeoCoV and PDF-2180-CoV share sufficient similarity with MERS-CoV across most of the genome,rendering them taxonomically the same viral species27,29. However, their S1 subunits are highly divergent compared with MERS-CoV (around 43-45% amino acid similarity), in agreement with their different receptor preference23.

In this study, we unexpectedly found that NeoCoV and PDF-2180-CoV use bat ACE2 as their functional receptor. The cryo-EM structure  of  NeoCoV  RBD  bound  with  the  ACE2  protein  from Pipistrellus pipistrellus revealed a novel ACE2 interaction mode that is distinct from how human ACE2 (hACE2) interacts with the RBDs from SARS-CoV-2 or NL63. Although NeoCoV  and PDF-2180-CoV cannot efficiently use hACE2 based on their current sequences, the spillover events of this group of viruses should be closely monitored, considering their human emergence potential after gaining fitness through antigenic drift.

Discussion:

The lack of knowledge of the receptors of bat coronaviruses has greatly limited our understanding of these high-risk pathogens. Our study provided evidence that the relatives of potential MERS-CoV ancestors like NeoCoV and PDF-2180-CoV engage bat ACE2 for efficient cellular entry.

However, HKU5-CoV and EriCoV seem not to use bat DPP4 or hedgehog ACE2 for entry, highlighting the complexity of coronaviruses receptor utilization. It was unexpected that NeoCoV and PDF-2180-CoV use ACE2 rather than DPP4 as their entry receptors since their RBD core structures resemble MERS-CoV more than other ACE2-using viruses (Fig. 4a, Extended Data Fig. 15).

Different receptor usage can affect the transmission rate of the viruses. Although it remains unclear whether ACE2 usage out-weight DPP4 usage for more efficient transmission, MERS-CoV appears to have lower transmissibility with an estimated R0 around 0.69. Comparatively, the ACE2 usage has been approved able to achieve high transmissibility. The SARS-CoV-2 estimated R0 is around 2.5 for the original stain, 5.08 for the delta variant, and even higher for the omicron

variant36-38. This unexpected ACE2 usage of these MERS-CoV close relatives highlights a latent biosafety risk, considering a combination of two potentially damaging features of high fatality observed for MERS-CoV and the high transmission rate noted for SARS-CoV-2. Furthermore, our studies show that the current COVID-19 vaccinations are inadequate to protect humans from any eventuality of the infections caused by these viruses.

Many sarbecoviruses, alpha-CoV NL63, and a group of merbecoviruses reported in this study share ACE2 for cellular entry. Our structural analysis indicates NeoCoV and PDF-2180-CoV bind to an apical side surface of ACE2, which is different from the surface engaged by other ACE2-using coronaviruses (Fig.4a).

The interaction is featured by inter-molecular protein-glycan bonds formed by the glycosylation at N54, which is not found in RBD-receptor interactions of other coronaviruses. The different interaction modes of the three ACE2-using coronaviruses indicate a history of multiple independent receptor acquisition events during evolution22. The evolutionary advantage of ACE2 usage in different CoVs remains enigmatic.

Our results support the previous hypothesis that the origin of MERS-CoV might be a result of an intra-spike recombination event between a NeoCoV like virus and a DPP4-using virus26. RNA recombination can occur during the co-infection of different coronaviruses, giving rise to a new virus with different receptor usage and host tropisms39,40. It remains unclear whether the event took place in bats or camels, and where the host switching happened.

Although bat merbecoviruses are geographically widespread, the two known ACE2-using merbecoviruses are inhabited in Africa. Moreover, most camels in the Arabian Peninsula showing serological evidence of previous MERS-CoV infection are imported from the Greater Horn of Africa with several Neoromicia species41. Considering both viruses are inefficient in infecting human cells in their current form, the

acquisition of the hDPP4 binding domain would be a critical event driving the emergence of MERS-CoV. Further studies will be necessary to obtain more evidence about the origin of MERS-CoV.

The host range determinants on ACE2 are barriers for cross-species transmission of these viruses. Our results show NeoCoV and PDF-2180-CoV favor ACE2 from bats of the Yangochiroptera group, especially vesper bats (Vespertilionidae), where their host belongs to, but not ACE2 orthologs from bats of the Yinpterochiroptera group. Interestingly, most merbecoviruses were found in species belonging to the Vespertilionidae group, a highly diverse and widely distributed family9.

Although the two viruses could not use hACE2 efficiently, our study also reveals that single residue substitution increasing local hydrophobicity around site 510 could enhance their affinity for hACE2 and enable them to infect human cells expressing ACE2. Considering the extensive mutations in the RBD regions of the SARS-CoV-2 variants, especially the heavily mutated omicron variant, these viruses may hold a latent potential to infect humans through further adaptation via antigenic drift42,43. It is also very likely that their relatives with human emergence potential are circulating somewhere in nature.

Overall, we identified ACE2 as a long-sought functional receptor of the potential MERS-CoV ancestors in bats, facilitating the in-depth research of these important viruses with zoonotic emergence risks. Our study adds to the knowledge about the complex receptor usage of coronaviruses, highlighting the importance of surveillance and research on these viruses to prepare for potential outbreaks in the future.


 

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