Genomic study of furin cleavage sites validates the natural evolutionary origin of SARS-CoV-2 in bats

In a recent study published on the bioRxiv* preprint server, a team of researchers describes the genomic region encompassing the furin cleavage site (FCS) in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Genomic determinants of Furin cleavage in diverse European SARS-related bat coronaviruses. Image Credit: Rudmer Zwerver / Shutterstock.com

Background

SARS-CoV-2 belongs to the species of severe acute respiratory syndrome-related coronaviruses (SrCs) of the subgenus Sarbecovirus. As compared to other sarbecoviruses and mammalian coronaviruses (CoVs), SARS-CoV-2 is highly transmissible due to a functional polybasic FCS between the S1 and S2 subunits of its spike (S) glycoprotein. FCS makes SARS-CoV-2 unique among other SrCs, as even the closest relatives of SARS-CoV-2, including the bat coronavirus RaTG13 and the pangolin COVs, do not have an FCS.

FCS is also considered essential in establishing SARS-CoV-2 infection in humans, as it determines the efficiency of infection of the upper respiratory tract and consequent transmissibility of SARS-CoV-2. More importantly, the existence of FCS has led to various hypotheses regarding the evolution of SARS-CoV-2, including speculations about the possibility of an unnatural origin from laboratory experiments.

About the study

The researchers of the present study amplified an 816-nucleotide fragment of the viral ribonucleic acid (RNA)-dependent RNA polymerase (RdRp) of ten European bat-associated CoVs belonging to the species SrC. They investigated the genomic regions encompassing FCS in these CoVs to determine the similarities/differences in this region as compared to other sarbecoviruses and mammalian coronaviruses.

The researchers accessed and used stored fecal samples from four horseshoe bat species including Rhinolophus hipposideros, R. euryale, R. ferrumequinum, and R. blasii, all of which are natural hosts of SrC,. These samples were collected from Italy, Bulgaria, Spain, and Slovenia between 2008 and 2009.

There are two distinct types of avian influenza A viruses (IAVs), namely the low-pathogenic avian influenza viruses (LPAIs) and high pathogenic avian influenza viruses (HPAIs). In HPAIs, a polybasic FCS at the hemagglutinin (HA) cleavage site already exists.

However, LPAI evolves into HPAI by acquiring an FCS via different molecular mechanisms. These include recombination with cellular or other RNA molecules and multiple nucleotide insertions/substitutions, which are facilitated by a stem-loop secondary RNA structure enclosing the FCS and a high adenine/guanine content in the external loop structure.

Study findings

One of the notable observations about the European bat-associated CoVs was that only 10% and 11% of these viruses showed an FCS in either the S2’ or the S1/S2 genomic region, respectively, thereby suggesting a broad genetic diversity in their genomic region encoding FCS. These CoVs, except for a few Middle East respiratory syndrome (MERS)-related CoVs, did not have an FCS at the S1/S2 boundary, thus suggesting that an FCS may not provide a fitness advantage in most bat hosts.

Furthermore, upon comparing sequences of the S1/S2 genomic region, remains of a polybasic FCS motif at the S1/S2 boundary in 12 of the 17 CoVs from Europe, Asia, and Africa were seen. This observation indicates a higher genetic diversity in European bat-associated SrC as compared to Asian bat-associated SrC.

Studying RNA secondary structures among some European bat-associated SrC and HPAI sequences revealed similarities in the genomic determinants of FCS acquisition between avian HPAI and bat SrC. Additionally, an adenine (A) to guanine (G) transversion in the external loop of the RNA secondary structure allowed furin cleavage in two European bat-associated SrC.

The genome sequencing results showed A to G transversion in 0.004% and 0.006% of the total genomic sequences in both these viruses. Furthermore, the researchers observed that single nucleotide substitutions in LPAI occurred at a low frequency of 0.0028%, thus indicating how FCS emerged in European bat SrC strains. Taken together, careful examination is needed to determine whether bat SrC quasispecies harbor a functional FCS exist within European bat.

In another European SrC, a stem-loop structure with more than 60% adenine/guanine content was observed, which facilitated the acquisition of an FCS comparable to the insertion leading to HPAI outbreaks in the United States in 2016-2017. The existence of the palindromic sequence CAGAC in some other European SrC, as compared to SARS-CoV-2, suggests that this genomic region might be serving as an RNA signal for recombination. More importantly, the recombination of European SrC was observed with another bat CoV HKU9, which would have resulted in the origin of S1/S2 FCS of SARS-CoV-2.

Conclusions

To conclude, the study results support the notion that FCS was acquired in European bat-associated SrC through mechanisms that are similar to the origin of HPAI in their avian reservoir. This observation further validates a natural evolutionary origin of SARS-CoV-2 in bats, with or without the involvement of intermediary hosts.

In the future, ecological studies on bats may identify other sarbecoviruses harboring functional FCS in bat hosts. Therefore, further investigation of the potential of these sarbecoviruses posing threats to human health is crucial.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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