Is COVID-19 becoming less virulent? Chinese scientists have discovered new sequences | viruses | Chinese scientists
"In terms of using human cell resources to synthesize viral proteins, COVID-19 did not evolve in the direction of the highest efficiency and the best mechanism, but showed an evolutionary trend of 'de optimization'." On June 25, Lu Jian, a professor of Peking University, introduced in an interview with the Science and Technology Daily reporter that this conclusion came from his cooperation with Qian Zhaohui, a research group of the Chinese Academy of Medical Sciences, who analyzed more than 9 million high-quality COVID-19 sequencing sequences.
"There is a process of mutual game between COVID-19 and human cells in resource competition, and the current mutant strains show a trend of 'moderate' use of human cell resources." Lu Jian introduced that the relevant research results have been published in the international journal Advanced Science a few days ago.
What inhibits the replication efficiency of Omicron
The essence of virus survival is to use protein synthesis machines within host cells to assemble more virus offspring. According to common sense, the evolution of viruses should make assembly work more efficient and smooth.
"After analyzing the sequencing sequence of more than 9 million COVID-19 viruses, we observed a trend of 'de optimization' of codon use." Lu Jian explained that "de optimization" is the change of virus sequence, which makes it more and more difficult to synthesize proteins in human cells, as if he dug more holes for himself, limiting the speed of viral protein synthesis.
Why are the assembled proteins the same, but the speed is getting slower and slower? "This is because species have a preference for codon usage, and the efficiency of different codons varies when translating the same protein." Lu Jian said that almost every amino acid has more than one codon, just like using different "synonyms" to express a meaning. The more "synonyms" human cells prefer to use, the more optimized they are, and the faster the protein synthesis speed is. Conversely, optimizing is the opposite.
The team analyzed the sequences of branches such as BA.2.12.1, BA.4/5, and XBB.1.5 in Omicron and found that the optimization ratio of Omicron was only about 60%, far lower than most human genes. Therefore, when using human ribosomes to synthesize proteins, the Omicron family cannot fully open up production capacity, which may inhibit the replication and transmission efficiency of the virus.
The team also evaluated 70 pairs of COVID-19 sequences in vitro through the experimental method of double luciferase. The results showed that COVID-19 preferred codons tended to enhance the efficiency of protein expression, while non preferred codons reduced the efficiency of protein expression, further confirming the impact of sequences on translation efficiency.
New findings help optimize the COVID-19 vaccine
In the past, it was believed that synonymous mutations in gene sequences would not affect cell function and biological adaptability as they do not alter protein sequences. However, this study revealed for the first time the influence of synonymous mutations of COVID-19 on the efficiency of viral protein expression on a large scale, and further proved that synonymous mutations can affect many biological processes, including the structure and stability of mRNA, the efficiency of protein translation and protein folding.
So why does COVID-19 have such a change? "There are special protein families in human cells that can mediate the changes of bases in the gene sequence of foreign viruses. We believe that it is this editing system in the human body that reduces the translation efficiency of viral proteins by changing the viral sequence and introducing non preferred codons, so as to fight against viruses." Lu Jian said that since the epidemic, the pathogenicity of COVID-19 has generally shown a weakening trend, and the importance of optimizing the viral codons in it needs further research.
"When designing the sequence of COVID-19 vaccine, we should consider the characteristics of codon optimization of mutant strains, master the evolution law of virus sequence, and improve the immune efficiency of vaccine." Lu Jian said that both mRNA vaccine and protein recombinant vaccine need to optimize the sequence to become a "high imitation" of virus. According to the laws revealed in this study, the team proposed the optimization strategy of COVID-19 vaccine. At present, experiments are being carried out to prove that the optimized vaccine sequence can effectively reduce the vaccine dose.
Previously, there was a view that the increasingly weak toxicity of COVID-19 was the result of active adaptation to humans. New research suggests that it may be the result of the game between COVID-19 and host cells. Whether it is the immune pressure brought by the immune barrier or the self-protection mechanism in cells, there may still be many unknown games between humans and viruses. Lu Jian believes that a deeper analysis of the virus sequence will uncover unexpected answers. For this reason, the team is still conducting evolutionary research on monkeypox virus and other viruses with collaborators.
