Are Thais and Cambodians genetically related

The genome of Sars-CoV-2 is not unusual. This illustrates the danger posed by naturally occurring coronaviruses

New coronaviruses that are closely related to Sars-CoV-2 have been identified in bats. They show how the pandemic virus could have originated.

Calming, threatening or fascinating? In a new preprint on the virological.org website, scientists are comparing the spike proteins of various Sars-CoV-2-related coronaviruses, including some that were unknown until recently. The analyzes show that Sars-CoV-2 is genetically not as unusual as it is sometimes claimed by proponents of the thesis of a laboratory development. In fact, the genetic diversity of the viruses related to it is great in nature, which once again speaks for a natural origin of Sars-CoV-2. However, this underlines the real existing pandemic risk posed by this virus family that is widespread in nature.

The researchers led by the Australian virologist Edward Holmes analyzed two prominent areas of the spike protein or its gene in detail: on the one hand the so-called receptor-binding domain (RBD), and on the other hand a sequence motif on which the protein is cut into two parts. The specific structure of these two bodies is essential for the resounding success of Sars-CoV-2 in humans.

The RBD is where the virus attaches to human cells. If its three-dimensional shape does not match that of the receptor, the virus cannot attach itself and infect the cell. The Sars-CoV-2 RBD fits the human ACE2 receptor just as well as that of the pangolin, but also the receptors of bats, ferrets, cats and raccoon dogs, for example. Ordinary laboratory mice, on the other hand, cannot infect it. For animal experiments, the human receptor has to be “built in” using genetic engineering methods.

The RBD is necessary for Sars-CoV-2 to contact the cell. However, in order for the virus to complete the infection and introduce its genetic material into the cell, it still has to fuse with the cell membrane. To do this, the spike protein must be activated, i.e. in this case split into two parts, called S1 and S2. (S2 is then cut again.)

The location of the interfaces is fixed - but not their sequence. This determines which endogenous “scissors” enzymes can perform the cut - and here Sars-CoV-2 has a great advantage: its interface, a so-called “furin cleavage site”, allows cutting by a whole range of enzymes that are common occur in the body. The virus is quickly and easily activated and ready to infect cells. In contrast to Sars-CoV-1, for example, whose S1 / S2 interface could only be cut by more specific enzymes and which was significantly less contagious.

The fact that the genetics of the spike protein of Sars-CoV-2 fit so well with humans is used again and again as an argument for a laboratory origin of the virus. The combination of RBD and S1 / S2 interface, which seemed ideal for the infection of humans, seemed suspicious to some. At the beginning of the pandemic, however, virtually no viruses closely related to it were known. That has changed in the meantime, says Silke Stertz from the Institute for Medical Virology at the University of Zurich, because scientists are actively looking for such viruses - and the more related viruses you know, the less specific Sars-CoV-2 appears.

This was also shown in the now published comparison of newly identified bat viruses from Cambodia, Thailand and Japan with Sars-CoV-2 and other corona viruses closely related to it. The spike protein of the Thai bat virus is 99 percent identical to that of a virus called RmYN02, which has been known for a long time and was isolated from a bat in Yunnan Province in China. This in turn is very similar to Sars-CoV-2. The same is true for the RBD of the virus originating from Cambodia. According to the researchers, that of Sars-CoV-2 interacts directly with the human ACE2 receptor in 18 places; the Cambodian virus has 15 of them - as many as the pangolin virus, which previously had the most Sars-CoV-2-like RBD.

Which species the bat virus can bind to has not yet been investigated in the laboratory. However, according to the researchers, it can serve as a further indication that Sars-CoV-2 is not necessarily specifically adapted to humans. This also indicates that the Sars-CoV-2 RBD has changed in the course of the pandemic due to mutations that have each allowed the virus to infect people more easily. So it is still in the process of optimally adapting to humans as hosts, as the researchers conclude.

The pangolin virus also has a special sequence motif directly in front of the S1 / S2 interface, which is found in both Sars-CoV-2 and its closest bat relative to this day, a virus called RaTG13, which is found in the same bat cave in Yunnan was isolated like RmYN02. It could be that this sequence helps guide the scissors to the cleavage site and thus also helps to improve cutting efficiency. In the case of RmYN02 and the Thai bat virus, the researchers found changes at the interface itself that are similar to the “furin cleavage site” of Sars-CoV-2. These are also already known from other coronaviruses that are less closely related to Sars-CoV-2, says Stertz. This genome area appears to be a hotspot for mutations, the researchers conclude.

The diversity of the sequence motifs identified so far and the genetic variations of viruses closely related to Sars-CoV-2 show quasi transitional forms or stations on a possible path to the “furin cleavage site”, says Stertz. Holmes and his colleagues also emphasize that their analysis strengthens the thesis of a natural origin of Sars-CoV-2.

However, it also clearly shows how large the diversity of potential pandemic viruses from this group of viruses is likely to be.