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Scientists have discovered antibodies that attack the “dark side” of the flu virus.
Influenza viruses have a mushroom-shaped protein known as neuraminidase (NA) that is said to have a “dark side” because the structure beneath its fungal coat has been largely unexplored by science. Antibodies that latch onto this dark side could help form the basis of antiviral drugs and vaccines that work against many flu virus, researchers wrote in a paper published Friday (March 1) in the journal Immunity.
Currently, flu vaccines are designed to target a different structure on the surface of flu viruses: hemagglutinin (HA). This lollipop-shaped protein allows viruses to attach to the outside of human cells and then infiltrate them. But it mutates quickly, which is why The flu vaccine should be updated every year. to match the HAs of circulating flu strains.
Related: Never-before-seen antibodies can attack many flu viruses
In comparison, the dark side of NA does not mutate as quickly and looks very similar in different strains of the flu virus, according to a study. statement from the National Institutes of Health (NIH).
NA is thought to help flu viruses navigate to their preferred receptor on the outside of host cells. Then, once a virus has infected a cell and multiplied inside, NA helps those new viruses leave the cell. Various antiviral medications for the flu, including Tamiflu (generic name oseltamivir), actually work by inhibiting NA and thus preventing flu viruses from escaping the cells they have infected. Therefore, mutations that modify the structure of NA can cause viruses less vulnerable or resistant to such drugs.
Scientists have only discovered a handful of human antibodies against NA, and these generally attach to the top or side of the fungal shell of the protein, the researchers noted in their report. These parts of the fungus are more likely to mutate in ways that help flu viruses evade the effects of antiviral drugs, they added.
In their new study, NIH scientists analyzed blood taken from two people who had been infected with H3N2, a subtype of influenza A virus that spreads seasonally and mutates especially rapidly. In the blood samples, the team identified six antibodies that attach to the dark side of NA.
In laboratory tests, these antibodies attached to several different H3N2 viruses and slowed their replication. The antibodies also worked against a different type of influenza A, called H2N2.
In experiments with mice, the antibodies saved many rodents from a lethal dose of the H3N2 virus, suggesting they could be useful for preventing and treating influenza in people. The antibodies showed strong protection both when administered to mice before infection and when administered afterward. The team also tested how the antibodies worked against some drug-resistant flu strains and found that they still showed the same degree of protection.
To better understand how these antibodies work, the researchers used cryogenic electron microscopy (cryo-EM), a microscopy technique that uses electron beams to reveal detailed three-dimensional structures of the molecules. The team used this to amplify two of the antibodies as they took over NA. The experiment showed that the two antibodies target different parts of the dark side that do not overlap.
This suggests that multiple features of the dark side could be targeted with future drugs or vaccines, and opens up the possibility of targeting multiple regions at once, for example.
“Our findings help guide the development of effective countermeasures against ever-changing influenza viruses by identifying hidden and conserved sites of vulnerability in the lower NA,” the study authors wrote.
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