[Research] The Chinese Academy of Sciences Qian Wenfeng's team found new evidence that "Omicron variants may come from mice"!

This article is original by Translational Medicine Network, please indicate the source for reprinting Author: Daisy Introduction: The COVID-19 pandemic has caused major diseases and deaths worldwide
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The SARS-CoV-2 Omicron variant was first reported in South Africa on November 24, 2021, and the World Health Organization designated it as a variant of concern within two days
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The proximal origin of omicron quickly became the subject of intense debate in the scientific and public health communities, leading to three prevailing hypotheses about its evolutionary history, the first of which is that omicron may have "spread secretly" and was underserved by viral surveillance and sequencing.
spread among the population
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Second, Omicron may have evolved in chronically infected COVID-19 patients
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A third possibility is that Omicron may have accumulated mutations in non-human hosts and then jumped into humans
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Currently, the second scenario represents the most popular hypothesis regarding the proximal origin of Omicron
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Recently, the team of Qian Wenfeng of the Chinese Academy of Sciences revealed a new piece of evidence that "Omicron variants may come from mice"
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Qian Wenfeng's team from the Chinese Academy of Sciences in Beijing recently reported intriguing new evidence that the Omicron variant may have come from mice
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Their paper, which was published on the BioRxiv preprint server, was quickly picked up and published in the Journal of Genetics and Genomics a few days later, and disproved the prevailing theory that Omicron's polymutated spike sequence must have occurred in a severe of immunocompromised patients evolved under prolonged infection
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https:// Their main idea is that mice may have somehow been infected with a human virus through "reverse zoonotic transfer" and subsequently The virus evolved all or most of its 45 new mutations before transferring back to humans
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This theory may explain why Omicron appears so abnormal in the phylogenetic tree, but there is a major problem: the mouse homolog of the human ACE2 receptor (hACE2), which viruses normally use to enter cells, has no effect on the standard The SARS-CoV-2 spike protein has little affinity
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To study the virus in this preferred research animal, scientists had to artificially introduce hACE2 to create mice that exhibited any significant respiratory distress when infected
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These transgenic mice were created in several ways, each exhibiting unique tissue tropism, penetrance, and correspondingly different effects
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The researchers performed knock-in experiments to integrate the human hACE2 sequence into the host genome and induce it under the control of several different promoters
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Adenovirus can also be used to infect cells and generate replication plasmids that reproduce the hACE2 encoding
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Given these questions, how did the standard human virus take root in mice? Several things are clear about how Omicron's sequence and disease sequelae differ from the other four variants
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While Omicron appears to be more contagious, it doesn't appear to be as serious -- it doesn't seem to target different cell classes in the deep lung in the same way
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These cell types may include bronchiolar and alveolar epithelial cells, alveolar macrophages, and various designated lung cells
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One possible explanation is that Omicron does not depend on ACE2 uptake and subsequent cleavage of TMPRSS for infection
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Instead, it appears to prefer direct endosomal uptake and cleavage by cathepsins
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The researchers reasoned that if Omicron did evolve in mice, the detailed details of the 45 mutations it acquired in mice should reflect this directly
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In other words, since each organism has different DNA repair mechanisms, nucleotide abundances, codon preferences, oxidative backgrounds, and other propensities for mutation, the "molecular profile" of its mutations should reveal species-specific features
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Actually, it's a tough task
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Nonetheless, the researchers used Omicron to trace back 12 possible base pair substitutions (i.
e.
, A>C, T, or G, C>A, T, or G, etc.
) during the evolution of Omicron from its most recent ancestor, B.
1.
1.
529 virus host
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They found that Omicron's molecular mutational spectrum is markedly different from that of all other viruses that have evolved in human patients, but is very similar to the molecular mutational spectrum associated with viral evolution in mouse cells
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While it has also recently been suggested that Omicron may have arisen after a brief incursion by an intermediate host such as mice or even deer, this study is "the first time real meat has been placed on the bones of this zoonotic two-step approach.
"
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The researchers believe that the observed mutations, as well as insertions and deletions, may be consistent with about a year of evolution in mice
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However, estimating mutational lag times like this is notoriously difficult and often somewhat subjective
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The molecular profiles of coronaviruses that have evolved in different host species were further characterized and compared to those of Omicron
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Specifically, 17 mouse hepatitis virus sequences, 13 canine coronavirus sequences, 54 feline coronavirus sequences, 23 bovine coronavirus sequences, and 110 porcine delta coronavirus sequences were retrieved
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The molecular profile of post-outbreak Omicron mutations (known to accumulate in humans) lies within the 95% confidence ellipse interval for humans
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In contrast, the molecular profile of pre-breakout Omicron mutations is within the mouse oval, suggesting that the pre-breakout mutations that accumulate some of these mutations in rodent (particularly mouse) hosts, and the associated viral repertoire they provide, are rather strange
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For example, insertion of a furin protease cleavage site in SARS-CoV-2 to gain an additional key arginine in Omicron remains unexplained, a modification that appears to further enhance furin processing during the viral life cycle
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Now, however, a new series of studies suggest that the evolution of furin protease cleavage sites from thin air may not be as large as previously thought
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At this point, European bats were shown to have a coronavirus that is only one mutation away from the polybasic furin cleavage site at the S1/S2 spike position
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Other features of Omicron include evasion of vaccine and antibody therapy, but not T-cell responses
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On the other hand, syncytia formed by rampant cell fusion were not observed in Omicron, which may explain why it is less severe
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If Omicron does switch to mice, what kind of mice is it? That is, is it a wild mouse or a lab mouse? If the latter, is it the whole mouse or just the cells from the mouse? Back in 2007, researchers showed that they could completely engineer SARS-CoV-1 in humans to infect mice, where the virus caused respiratory damage after 15 consecutive transmissions in animals
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Ralph Baric et al.
recently did this for SARS-CoV-2 in just 10 segments
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These manipulations apparently accelerated evolution several times over that might have occurred in the natural environment
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That's exactly why this is done
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In cell culture, things can be done faster
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The same kind of illustrative molecular mutational profiles studied in Omicron described above may also be evident after passage in specific cell lines
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In other words, the characteristics of the virus can be easily evolved under specific culture conditions according to the needs and preferences of the specific cell line used
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For example, Delta variant infection was 4-fold higher than Omicron infection in Calu-3 cells (human lung adenocarcinoma epithelial cells), which have high expression of TMPRSS and favor the cell surface infection pathway
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On the other hand, in HEK cells (human embryonic kidney cells), which are most suitable for entry into endosomes, Omicron infection was 10-fold higher than delta
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When potentially mixed transgenic cell lines expressing receptors from different species are thrown into the mix, it's hard to know what happens
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Reference: https://medicalxpress.
com/news/2022-01-omicron-mouse-kind.
html Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment plans
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For health guidance, please go to a regular hospital for treatment
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