Tracing adaptation to ACE2 use in sarbecoviruses – News-Medical.Net

A detailed study published on the preprint server bioRxiv* in July 2020 argues that recombination accounts for the appearance of the ability of both SARS-CoV and SARS-CoV-2 to use the human angiotensin-converting enzyme (hACE) 2 as the binding receptor mediating viral infection of human cells. This helps understand how this common trait is present in both otherwise diverse viruses. It also emphasizes the need to watch out for new outbreaks of human pathogenic sarbecoviruses in south-western China and Africa, among other regions.
SARS-CoV and SARS-CoV-2 are Quite Different
The current COVID-19 pandemic is caused by the viral agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the similarity of the name of this coronavirus with that of the earlier SARS pathogen, namely, SARS-CoV, the two are not in the same line of descent. Scientists are thus suspicious of the group of coronaviruses (CoVs) in the subgenus Sarbecovirus that includes both these viruses as well as many bat viruses and a few pangolin viruses, as a potential source of many new pathogens.
Both the SARS viruses cause infection by actions mediated by viral binding to the ACE2 molecule, and this means this particular trait is essential to arrive at a proper understanding of how sarbecoviruses became able to infect humans. There are bat SARS-like CoVs which are in a close phylogenetic relationship with SARS-CoV but cannot bind human ACE2. Conversely, another bat SARS-like CoV can.
ACE2 Binding Ability
The ability to bind human ACE2 is, therefore, traceable to the presence of a couple of amino acids in the receptor-binding domain (RBD) of the virus. The deletion of these residues causes significant structural differences that cause them to lose this ability. The question facing the researchers in the current study is since these are all closely related, how did some of them acquire this ability?
The current hypothesis is that Chinese horseshoe bats, which have been shown to harbor many different sarbecoviruses are the primary natural reservoir for this subgenus. These are also considered the primary host for the ancestor of SARS-CoV, as a number of very similar viruses have been isolated from them. Some scientists think that SARS-CoV acquired recombinant genomic regions from different SARS-like CoVs in the area in and near Yunnan province in China, and then leaped into humans, crossing species barriers.
The Spike Gene
One particular newly acquired region in the SARS-CoV is the spike gene, as shown by the presence of a breakpoint at the point where the ORF1b meets the spike. This spike has a markedly different genetic makeup compared to the spike proteins of other viruses in the same clade. The primary variation is in the large deletions in the RBD mentioned above. The recombinant region is considered to have been acquired from an unknown line of sarbecoviruses and made it possible for the SARS-CoV to emerge as a human pathogen. This event has been demonstrated to occur in the spike genes of other CoVs, which have then caused infection in humans and domestic animals, and recombination is a vital process in driving the emergence of all CoVs.
Structural modeling of sarbecovirus RBDs found in Uganda and Rwanda. (A) Structural superposition of the X-ray structures for the RBDs in SARS-CoV-1 (PDB 2ajf, red)

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