SARS-CoV-3 is upon us

Chinese researchers from Sun Yat-Sen University, Fudan University, Yunnan Institute of Endemic Disease Control and Prevention, Yunnan University, National Institute for Viral Disease Control and Prevention-Beijing, City University of Hong Kong along with Australian scientists from University of Sydney have discovered a recombinant strain of SARS-CoV-2 and SARS-CoV-2 viruses in bats found in the Yunnan province of China.

The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2022.11.23.517609v1
 

We have characterised the mammalian-associated virome of individual bats. This revealed an unexpectedly high frequency of co-infection, with approximately one-third of the virus-positive individuals simultaneously infected by two or more viruses.

The frequency of co-infection in individual bats has seldom been investigated, and only a few studies have explored the co-infection of specific viral species using consensus PCR methods (e.g., paramyxovirus, ref 18). As such, this study provides the first empirical evidence for co-infection using an unbiased omics approach.

Co-infection is prerequisite for virus recombination or reassortment 8, and the gut microbiome can facilitate the recombination of enteric viruses 19. Hence, the high frequency of co-infection observed here suggests that recombination and reassortment are very likely to happen within individual bats, which in turn may facilitate the emergence of zoonotic viruses 9.

Our results also revealed frequent virus spillover among different bat species, identifying 12 different viral species from different families that infect multiple host species. The ability of viruses to jump host species boundaries appears to be a near universal trait among viruses 20.

Our results are of note because they show that the probability of virus spillover among pairs of host individuals is negatively associated with host phylogenetic and geographic distance, thereby supporting the hypothesis that phylogenetically related or spatially closely located hosts share more viruses 21,22.

The frequent virus spillover among phylogenetically related or spatially co-located bats provides an opportunity for viromes of different bat species to exchange, further expanding genetic diversity of circulating viruses.

We identified two SARS-related coronaviruses in Rhinolophus bats (Rh. marshalli, Rh. pusillus Rh. thomasi, and Rh. macrotis) which we suggest are at particular risk for emergence. One of the SARSr-CoV – Bat SARS-like coronavirus BtSY2 (i.e., BtSY2) – is related to both SARS-CoV and SARS-CoV-2 and likely to have a history involving recombination.

Notably, there are only five amino acid differences in the receptor-binding domain (RBD) of spike protein of this virus compared with SARS-CoV-2 strain Wuhan-Hu-123, which makes it the closest relative to SARS-CoV-2 found in China in this particular genomic region.

In contrast, the nsp7∼nsp11 proteins of ORF1a and nsp12∼nsp14 protein of ORF1b were closely related to SARS-CoV, indicating that these genes were likely to be acquired from another SARSr-CoV. The remainder of its genome was closely related to SARS-CoV-2 and to several bat coronavirus previously found in Yunnan, including RaTG1313, RmYN0215, and RpYN0614 that are all close relatives of SARS-CoV-2.

Together, these findings strongly suggest that virus spillover and co-infection in related bat species contribute to the recombination of potentially pathogenic coronavirus and could possibly facilitate virus emergence in other species.

Functional analysis indicated that Bat SARS-like coronavirus BtSY2 likely has the ability to the bind human ACE2 receptor, and even has slightly higher affinity than SARS-CoV-2 Wuhan-Hu-1.

Three of the five substitutions in the RBD – Q498H, N501Y and H519N – have been reported to increase affinity to human ACE224, and notably, the N501Y substitution is present in the Alpha, Beta, Gamma and Omicron variants of SARS-CoV-2. In addition, we found that the nsp7-nsp14 proteins (in which nsp12 is the replicase, i.e., RdRp) of BtSY2 were closely related to those of SARS-CoV.

A comparative study showed that SARS-CoV can replicate more rapidly than SARS-CoV-2 in vitro 25, while another suggested that nsp14 is likely associated with virulence 26. Hence, these data tentatively suggest that BtSY2 may be able to replicate rapidly with similar virulence as SARS-CoV. Although this issue merits further consideration, this virus is potentially of high risk of emergence and so should be monitored carefully.

We identified another four viruses of concern, likely to be pathogenic in humans or livestock.

Bat SARS-like virus BtSY1 is closely related to SARS-CoV 27,28. Rhinolophus bat coronavirus HKU2-like is closely related to SADS-CoV, which causes severe diarrhea and death in swine 29,30, Rotavirus A causes diarrhea in humans 31,32, while Mammalian orthoreovirus is known to have a broad host range and cause diarrhea in swine 33,34. Interestingly, all these viruses of concern were found in more than one bat species in our samples, suggesting that these potentially zoonotic viruses may have a broader host range or have a higher rate of spillover than other viruses.