In a study published in Science yesterday, scientists report a mutation in the Delta variant of SARS-CoV-2 that enables it to infect cells more effectively than the original virus strain. Unlike many studies of SARS-CoV-2 variants that have focused on changes in the spike (S) protein, the researchers used a technique that allowed them to identify effects from tweaks to other viral proteins as well. In this case, they identified a mutation affecting the nucleocapsid (N) protein as responsible for the increased infectivity.
Specifically, the study, conducted by Nobel laureate Jennifer Doudna of the University of California, Berkeley, and her colleagues, found that a mutation called R203M in Delta’s N protein significantly increased how much viral RNA made it into host cells.
The research team adapted a tool known as a virus-like particle, which contains the virus’s proteins but not its genome, reports Science in an article about the study. Without that RNA genome the particles can’t infect cells, and thus don’t require the stringent safety protocols needed to study SARS-CoV-2 directly. The research team modified the virus-like particles by inserting a piece of mRNA that makes host cells glow, acting as a visual indicator of infection.
The researchers built virus-like particles with proteins found in various SARS-CoV-2 variants to better understand how changes to those proteins affect the virus’s properties. In some experiments, the team recreated the mutation R203M found in Delta’s N protein. After measuring the brightness of cells exposed to the virus-like particles, the team concluded that a single amino acid change to the N protein “supercharged” the particles so that they delivered 10 times more mRNA into cells, Doudna tells Science. The team also tested a live coronavirus mutated with R203M on lung cells and found that the mutated virus induced the cells to produce 51 times more virions than the original strain of SARS-CoV-2.
The mutation improves the virus’s ability to insert RNA into cells, thus increasing the amount of infectious viral particles it produces in the host, reports Science. Shan Lu, a cell biologist at the University of California, San Diego, who was not involved in the research, tells the publication that “The field could think more about targeting the nucleocapsid protein to really help control infection and help treat patients.”
Michael Summers, a University of Maryland, Baltimore County structural biologist, tells Science that the team’s novel virus-like particle system “allows you to look at any mutation and its influence on key parts of viral replication. . . . That can now be studied in a much easier way by a lot more scientists.”
Rockefeller University virologist Charles Rice cautions, though, that virus-like particles can’t replace working with the real virus in advanced biosafety level labs, telling Science, “At the end of the day if you really want to understand how these mutations are affecting basic viral replicative processes, you have to put [a mutation] in the virus and study it.”