The Delta variant of the coronavirus is highly contagious. It is almost 2 times more contagious than the original strain of the virus that was detected in China and the other variants of interest or concern. It was detected in India in October last year and spread around the world through the travels of people who were infected. Already in August of this year the Delta variant was in 163 countries, and what makes it spread so quickly is being investigated.
Scientist Jennifer Doudna, winner of the 2020 Nobel Prize in Chemistry together with Emmanuelle Charpentier for the development of a method for gene editing, began to search for an answer to understand what was happening with the Delta variant. With his team, Doudna, who works at the University of California at Berkeley, United States, developed a laboratory strategy that allows the rapid and safe study of the effects of mutations in coronavirus variants.
He found that an inconspicuous mutation within the Delta variant allows the coronavirus to introduce more of its genetic code into host cells. This increases the chances that each infected cell will spread the virus to another cell. Doudna’s study was published in the journal Science, and provided a powerful tool both to understand current variants of the coronavirus and to explore how future variants could affect the evolution of the pandemic.
Until now, researchers from different laboratories around the world analyzed mutations in the coronavirus genome. They have focused on the Spike protein, which allows the virus to invade human cells. This is partly because working with the virus and doing studies requires high-level biosafety facilities. So to probe for individual mutations, what is called a “pseudovirus” is used, which is a construct made from a different virus, often a lentivirus, that can express a coronavirus protein on its surface. However, lentiviruses only express the Spiga protein. They do not express the other three structural proteins of the coronavirus.
What Dr. Doudna and her team now achieved was a new tool: they modify laboratory constructs called “virus-like particles (VLPs),” which contain all the structural proteins of the virus but lack its genome. From the outside, one of those particles looks the same as the whole virus. It can bind to cells in the laboratory and invade them. But because it is devoid of the virus’s RNA genome, it cannot hijack a cell’s machinery to replicate itself and leave the host cell to infect more cells. In this way, the virus cannot be spread in the laboratory.
Doudna’s team, which included Melanie Ott, a virologist and director of the Gladstone Institute for Virology, added an innovation to the VLP particle system. They inserted a fragment of messenger RNA that makes cells invaded by the particles light up and glow. The brighter the cells after being infected with the virus-like particles, the more RNA they have delivered.
After, the researchers modified the proteins in the particles with various mutations. One of them was R203M, a mutation found in Delta that alters the nucleocapsid (N), which is a protein hidden within the virus that packages its RNA genome. This protein plays a central role in viral replication.
They found that according to the intensity of the brightness of the virus-like particles, “A single amino acid change found in the Delta nucleocapsid protein supercharged the particles with 10 times more messenger RNA compared to the parent virus,” according to Doudna. Cells infected with virus-like particles carrying N mutations found in the Alpha and Gamma variants glowed 7.5 and 4.2 times brighter, respectively.
Next, The team of scientists tested a real coronavirus designed to include the R203M mutation, under suitable biosafety conditions in the laboratory. After invading lung cells in the laboratory, the mutated virus produced 51 times more infectious virus than a parent strain of the coronavirus.
“This mutation found in Delta makes the virus more efficient at producing infectious particles and thus spreads more rapidly,” said Abdullah Syed, a biomedical engineer at the Gladstone Institute for Data Science and Biotechnology, and one of the first authors of the article.
The researchers are now trying to understand how the Delta R203M mutation and others in protein N enhance the assembly of viral particles and their delivery of messenger RNA to host cells. For that, they will study whether a host protein is involved. If confirmed, a drug could be developed to stop the spread of Delta.
Consulted by Infobae, the virology researcher at the National Institute of Agricultural Technology and member of the Country Project, the consortium for genomic surveillance of the coronavirus in Argentina, biologist Humberto Debat, commented: “The new work of Dr. Doudna and her team is exceptional and elegant. They have generated a new tool for the study of the coronavirus that causes the current pandemic and could be applied to other viruses. It is extremely efficient, practical and safe. It will now allow viruses to be studied in common molecular biology laboratories and not only in those with biosafety level 3, where there are standards to be met to limit the risk of contagion ″.
The Argentine researcher pointed out that Doudna’s team focused on the four structural proteins of the coronavirus. “The work is transcendental because before, pseudoviruses were used in laboratories to study the spike protein of the virus. But the limitation was that it was not possible to study what happened in other proteins of the virus. Doudna’s contribution is to generate a tool and also to find that there are mutations in those other proteins that help make the variants more transmissible. Thanks to this work, the international scientific community now has a tool to test new mutations and their infectivity, among other processes that are very difficult to study in vitro. We are amazed at the results they have had. It could be used in the development of antiviral drugs. ”
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They detect a mutation within the Delta variant that explains its contagiousness