The virus accumulates mutations when it replicates in infected cells. Repeated replication can result in virus strains that show reduced pathogenicity. Such strains may function as vaccines if the attenuated virus can produce immunity without serious illness.
This approach is not new. Albert Sabin developed an attenuated poliovirus vaccine in the mid-20th century to help eradicate naturally occurring polio in the Western Hemisphere. Attenuated virus vaccines for rubella, measles, yellow fever and other illnesses are widely used.
Can a similar vaccine be developed for COVID-19?
Researchers at the University of Alabama at Birmingham do basic research on that possibility Virology Journal.. They asked a simple question: Which mutation predominates when the SARS-CoV-2 virus that causes COVID-19 propagates in tissue culture in the next generation (called virologist passage)?
UAB researchers have found that SARS-CoV-2 isolates adapt rapidly as they grow on repeated passages of VeroE6. cell, A strain of kidney cells commonly used for viral growth. The evolved virus gained higher infectivity, showed a faster spread of infection, and created dramatically larger plaques on Vero cells. Plaques are visible fragments of the cell layer in which cells are destroyed by the growth and release of the virus.
In the case of one of the SARS-CoV-2 strains tested by UAB researchers, the Washington state strain, the first COVID-19 virus detected in the United States in early 2020, an infection released from cells. The average number of sex virus particles was one-hundredth of the number of infectious particles released after four passages.
Researchers led by Dr. Ilya Frolov, a professor of the UAB Department of Microbiology, have discovered that the evolution of the virus was developed by two major mechanisms.The first was 7 inserts amino acid, Containing two positively charged amino acids, into a peaplomer of the Washington SARS-CoV-2 isolate. The virus uses spike proteins to attach to ACE2 receptors on cells, causing them to invade. Therefore, peplomer is a major determinant of pathogenesis.
The second mechanism was the change of one amino acid from serine to glycine in a peplomer near the cleavage site. This is a mutation called S686G.Both mechanisms increased the ability of the mutant to bind Heparan sulfate, Abundant on the surface of cells. The two changes also increased plaque size and spread rate. Its binding to heparan sulfate on the cell membrane appears to be the mechanism of primary viral attachment prior to the high affinity interaction of spikes with the cellular ACE2 receptor. As a test of biological importance, a solution of heparin (a related polysaccharide) inhibited the infectivity of the mutant virus, which showed increased binding to heparan sulfate, whereas heparin reduced the infectivity of the non-mutated virus. I didn’t let you.
To test the independent effects of the two major mechanisms, UAB researchers have put into DNA each a copy of the genome of the first Chinese Wuhan SARS-CoV-2 isolate sequenced in January 2020. I cloned the changes.The RNA copy constructs produced from these DNAs are delivered to the cells, which then virus.. Researchers have found that each single mechanism increases the binding of constructs to heparan sulfate, and that double mutant constructs with both changes have a significantly higher infection rate than any single mutant. I found.
“An important feature of the double mutant is that further evolution in cultured cells is unlikely,” Florov said. He found that the recombinant single mutant continued to accumulate various second-site mutations with further passages, while the double mutant containing both amino acid insertion and S686G was stable and made additional changes. He states that he did not win.
Interestingly, SARS-CoV-2 is a positive-strand RNA coronavirus. Alpha virus is also a positive RNA virus. Others like the alphavirus Chikungunya fever, Venezuelan equine encephalitis, Ross River, Sindvis, during cell culture growth, increased plaque size, stronger interaction with heparan sulfate, stimulated spread of infection, etc. It shows that it showed the rapid evolution of.
Importantly, these evolved alpha viruses were usually dramatically less pathogenic in mice and humans.
“Like other RNA + viral heparan sulfate-binding mutants, evolved SARS-CoV-2 can be attenuated in vivo and is a double mutant with the most adapted phenotype in particular.” Said Mr. Florov. “Therefore, they may also be used as the basis for the development of a stable live attenuated vaccine for COVID-19.”
In addition to Fluorov, the study was co-led by Dr. Todd Green (Associate Professor) and Dr. Elena Fluorova (Professor) of the UAB Faculty of Microbiology.
Nikita Shiliaev et al, a native isolate and recombinant SARS-CoV-2, rapidly evolve to higher infectivity in vitro through more efficient binding to heparan sulfate and reduced S1 / S2 cleavage. Virology Journal (2021). DOI: 10.1128 / JVI.01357-21
University of Alabama at Birmingham
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The COVID-19 virus can rapidly become infectious and less pathogenic during in vitro growth.
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