AdministratorApril 9, 2021 at 1:50 pm
What are the mutational steps that coronavirus would have to have made in order to jump into humans?
MemberApril 15, 2021 at 12:04 pm
When the CoV2 genome was just sequenced and made publicly available on January 10, 2020, it was a riddle, as no closely related strains were known. But quite quickly, on January 23, Shi Zhengli released a paper indicating that CoV2 is 96% identical to RaTG13, a strain which her laboratory had previously isolated from Yunnan bats in 2013. However, outside of her lab, no one knew about that strain until January 2020.
It was immediately clear that RaTG13 is special. Take a look at the figure below:
Next, pangolins appeared on the scene: in February, another group of Chinese scientists discovered a peculiar strain of pangolin coronavirus in their possession, which, while generally being only 90% similar to CoV2, in the RBM region was almost identical to it, with only a single amino acid difference (see the upper two sequences, dots indicate a match with the top sequence):
Surprisingly, in the first quarter of the S protein, the pangolin strain is highly dissimilar from CoV2, but after the RBM all three strains (CoV2, Pangolin, RaTG13) exhibit a shared high degree of similarity. Most strikingly, RaTG13’s RBM itself is quite different than that of CoV2, which can be seen from the steep dive of the green RaTG13 graph compared to the red CoV2 graph in the RBM region (pink strip) in the following graph:
MemberApril 15, 2021 at 12:22 pm
<b data-selectable-paragraph=””>A Killer Intro
It is impossible to ignore the introduction of a PRRA insert between S1 and S2: it sticks out like a splinter. This insert creates the furin cleavage site, which I mentioned at the very beginning. Let me explain what a furin site is. Remember the structure of our spike protein? Here is a detailed diagram:
The protein consists of two parts, S1 and S2, of which S1 is responsible
for primary contact with the receptor (recall Receptor Binding Domain /
Motif), and S2 is responsible for fusion with the cell membrane and
penetration into the cell. The fusion process is started by the fusion
peptide marked in yellow, but in order for it to engage in its dirty
deed, someone must cut the S protein at one of the sites marked by
diamonds in the diagram above. The virus does not have its own such
“cutters”, so it relies on various proteases of its victims. There are
several types of such proteases, as can be deduced from the abundance of
colors of those diamonds. But not all proteases are equal, and not all
types of cells have proteases needed by the virus. Furin is one of the
most effective, and it is found not only on the surface of cells, but
also inside. Most clearly, the danger of the new furin site is
demonstrated by the difference between CoV2 and its grandpa, SARS-CoV:
As can be seen from the diagram, in the case of CoV2, thanks to the furin site, it is not two, but three classes of proteases (three colored PacMans) that can cut its S protein outside the cell. But perhaps the most important difference is that furin is also present inside the cell, so it can cut the S protein immediately after virion assembly, thereby providing new virions with the ability to merge with new cells right off the bat (no pun intended).
The importance of the new furin site in CoV2’s virulence was recently demonstrated by a study in hamsters where the disappearance of the furin site (due to a mutation) greatly decreased mutant CoV2’s pathogenicity and replication ability:
Infection of hamsters shows that one of the variants (Del-mut-1) which carries deletion of 10 amino acids (30 bp) does not cause the body weight loss or more severe pathological changes in the lungs that is associated with wild type virus infection.
MemberApril 15, 2021 at 12:42 pm
It is important to discern that no researcher to researcher disagreement should be given weight, one way or another, because of political or national alignment or conformity to a consensus of a group. It is evidence and origin that is in question, and therefore there are many opinions.
“…In this case, despite research on viruses found in the animal
species sold at the Wuhan market, no intermediary virus between RaTG13
and SARS-CoV-2 has been singled out so far. Until one is identified and
its genome sequenced, the question of the origin of SARS-CoV-2 will
remain unanswered. For lack of convincing evidence concerning the last
animal intermediary before human contamination, some sources are
suggesting that the virus could have crossed the species barrier
following a laboratory accident or even be man-made…”
MemberApril 15, 2021 at 1:01 pm
<div> At this point I would leave all these discussions, and expect public media to mature to a point where the world can be freer from cover-ups, rash and incorrect conclusions and outright mistaken beliefs about health choices and preventative alternatives.
I would like to end my contribution to discussions and read what others have discovered. I leave you with this excerpt:
“.. Today, any laboratory can obtain or synthesise a gene sequence. It’s possible to build a functional virus from scratch in less than a month using sequences available in the databases. In addition, gene manipulation tools have been developed that are fast, easy to use and inexpensive. They enable spectacular progress, but at the same time multiply the risk and possible severity of an accident, in particular in gain-of-function experiments on viruses with pandemic potential.
Even if it ultimately turns out that the Covid-19 epidemic is the result of a “classic” zoonosis, incidents of pathogens escaping from laboratories have been documented in recent years. One of the best-known cases is the Marburg virus disease, which originated from contamination by wild monkeys. The 1977 flu pandemic is another example. Recent genetic studies suggest that it was caused by the leak of a virus strain, collected in the 1950s, from a laboratory. More recently, several such accidental leaks from studies of SARS-CoV have been reported in the literature. Fortunately, none of them caused a major epidemic.
International standards require that any research, isolation or culturing involving potentially pandemic viruses, including respiratory ones, must be conducted under secure experimental conditions, with irreproachable traceability in order to prevent any zoonotic transmission. However, accidents can always happen. It is important to consider the potential risk of such experiments, especially if they target gain of function or infectivity…”
AdministratorApril 15, 2021 at 3:40 pm
Very interesting – thank you
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