XBB strains are pathogenic or lower! The team from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, found that XBB acquired a new mutation with low cell lethality that was less toxic than other Omicron mutant strains

*For medical professionals only

The new crown virus seems to have become "stronger
".

With the new crown pandemic, the new crown virus continues to mutate and produce new strains, the recent emergence of XBB and its subvariants are recognized as the strongest immune evasion ability of the new crown variant so far, and the existing monoclonal antibody drugs may have completely failed
.

However, increased transmissibility does not imply increased
pathogenicity.
From the original strain to Omicron, from BA.
2/5 to XBB, has the new coronavirus become stronger or weaker?

This week, Xia Bingqing and Gao Zhaobing's team from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences published a paper on the preprint platform bioRxiv [1], analyzing and comparing the relationship between
mutation and pathogenicity of key strains of the new coronavirus.
The mutant P71L, which has the highest cell lethality rate, is almost non-existent in the milder Omicron strain, and T9I, which has a lower cell lethality rate, is highly conserved
in BA.
1-5.

Notably, XBB also retained a mild T9I mutation, in addition to obtaining a new low cell lethality mutation, T11A, with no high cell lethality mutation
observed.
These clues suggest that the pathogenicity of XBB should be further weakened in the various subvariants of
Omicron.

Thesis title map

Multiple variants of the new coronavirus have different pathogenicity, which is related to
the different mutations carried by different strains.
The novel coronavirus envelope protein (2-E) forms a group of pentameric protein channels that play an important role
in the pathogenic ability of the virus.

Previous studies have found that the new coronavirus envelope protein itself is enough to induce cell death in vivo, trigger cytokine storms, and even lead to acute respiratory distress syndrome (ARDS)-like damage
.
The high-frequency mutation T9I in the Omicron envelope protein has been shown to reduce viral replication and virulence
.

It can be seen that mutations in the envelope protein of the new coronavirus may be used to predict the evolutionary trend
of the pathogenicity of the new coronavirus.

The researchers screened mutations with mutation frequencies ≥0.
01% in the subvariants of Alpha, Beta, Gamma, Delta and Omicron, and analyzed their relationship
with cell lethality and disease severity.

Based on data from the National Genome Science Data Center (NGDC), a total of 92 mutations were screened, of which 4 mutations had a frequency of more than 1% and 2 had a frequency of more than 90%.

Omicron inherited 31 mutations from its "predecessors" and received 7 new mutations
.

Through in vitro experiments, the ratio of cell death to mutant protein expression level was calculated, and the cell lethality of different mutant envelope proteins was obtained, compared with wild-type envelope proteins, and the results showed that the lethality rate of 13 mutant cells was enhanced, the lethality rate of 51 mutant cells was weakened, and the lethality rate of 28 mutations did not affect the cell lethality rate
.

Cell lethality with different mutations

The researchers calculated the frequency difference (△Frequency) between the mutation frequency in the Omicron strain and the mutation frequency of the first four variants, analyzed the relationship with cell lethality, and found that all mutations could be clearly classified into three categories
.

The frequency difference of the first type of mutation was between -0.
2% and 0.
2%, containing 87 mutations
.
The researchers believe that this type of mutation has little effect on the viral phenotype
.
The aforementioned 28 mutations that do not affect cell lethality are all in
this category.

The second type of mutation contains two mutations, P71L and P71S, which can significantly increase cell lethality
.

The third type of mutation includes S50G, S55F and T9I, which have lower cell lethality and are more
frequent in Omicron.

Overall, the difference in mutation frequency is inversely correlated
with cell lethality.

Three types of mutations

Based on data from three clinical studies, the investigators quantified the relationship
between hospitalization rates, disease severity, and mutations.

As can be seen from the left of the figure below, in the less pathogenic Omicron, the frequency of the three types of mutations with lower cell lethality is higher
.
The frequency of T9I mutation in BA.
1 increased sharply to 99.
7%, and maintained a high proportion in BA.
1-5, while only 0.
17%, 0.
11% and 0.
06%
in Alpha, Beta and Delta, respectively.
Similarly, S55F, which has a low cell lethality rate, has a 4-fold
increase in frequency in Omicron.

As can be seen in the figure below, type II mutations with high cell lethality are more frequent in highly pathogenic strains
.
P71L first appeared in the alpha strain, increased its frequency to 99.
12% in the most toxic beta strain so far, and plummeted or even disappeared
in Omicron.
P71S similar
.

The right side of the figure below mainly involves different subvariants of Omicron, which can be seen to basically conform to the above rules
.
Compared with BA.
1/2, BA.
4/5 had heavier clinical symptoms, and the frequency of P71L mutations with high cell lethality increased and the frequency of T9I mutations in low cell lethality decreased
slightly.

Mutation frequency, hospitalization rate, and disease severity

The researchers believe that from the above results, it can be assumed that 5 mutations in the second and third types of mutations can be used to analyze the pathogenicity
of the new coronavirus.

Subsequently, the researchers analyzed six new subvariants that emerged after BA.
5, including BA.
5.
2 and BF.
7, which are predominantly circulating in China, and the XBB strain,
which has recently attracted much attention.

In BA.
5.
2, the T9I frequency is 91.
68%, S55F is 0.
8%, and P71L is reduced to 0.
02%; In BF.
7, the T9I frequency is 91.
44%, S55F is 0.
15%, and P71L is 0.
05%.

In XBB, there is no class II mutation, T9I still maintains a high frequency of 91.
39, and XBB also obtains a new mutation, T11A, with a frequency of 90.
59%.

T11A has previously been shown to be a dominant negative mutation in envelope protein channel function, impairing channel activity and significantly reducing cell death and cytokine release
.

Analysis of pathogenicity-related mutations in 6 new variants

The experimental results in mice showed that compared with the wild-type envelope protein, the toxicity of T11A mutant protein was significantly weakened, the lung function of mice was less impaired, inflammatory cell infiltration, edema, pulmonary interstitial hyperemia, hemorrhage, alveolar collapse and other pathological manifestations were greatly reduced, and the expression levels of cytokines and chemokines were also significantly reduced
.

The toxicity of the T11A mutant envelope protein was significantly reduced

Based on the above results, the researchers believe that the pathogenicity of the XBB strain will be further weakened compared with the previous Omicron subvariant.

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The author of this article Dai Siyu