A tetramer of the influenza neuraminidase protein (shown in blue and light blue) bound by variable domains of two new human antibodies (shown purple/pink and brown/beige) targeting its “dark side.” Viewed along with 4-fold axis of NA tetramer with its catalytic sites facing up. Credit: NIAID
Key points:
- The “dark side” of the influenza neuraminidase (NA) protein head makes it vulnerable.
- Researchers isolated human antibodies targeted against the NA dark side from two people who had recovered from influenza type A subtype H3N2 and found that the antibodies inhibited propagation of several influenza viruses.
- The unique antibody targets provide new opportunities for vaccine development and other therapeutic strategies.
Researchers have identified antibodies that target a hidden region of the influenza virus. Their discovery, outlined in Immunity, sheds light on the unexplored “dark side” of the neuraminidase (NA) protein head and suggests a new target for vaccination against influenza.
Each season, scientists must update the influenza vaccine to provide protection against the many strains and subtypes of the rapidly evolving virus. To improve vaccines and protect against a broad range of viruses, researchers need to identify new targets on the virus’s surface protein in conserved regions. The underside of the influenza NA protein head contains a highly conserved region—called the “dark side”—with targets that make it vulnerable to antibody binding and inhibition.
In this study, researchers isolated human antibodies targeted against the NA dark side from two people who had recovered from influenza type A subtype H3N2. They found that the antibodies inhibited propagation of viruses from subtype H2N2 and H3N2 viruses from humans, swine, and birds.
Researchers also injected mice with a lethal H3N2 virus subtype and treated them with the antibodies either 1 day before or two days after infection. In both cases, the antibody showed the potential to treat and prevent influenza in a mouse model.
Using cryogenic electron microscopy, the team analyzed the antibody structure and determined that each antibody targeted different, nonoverlapping regions of the NA dark side. This finding indicates that the dark side region has multiple areas that could be useful targets to explore for vaccine development and other therapeutic strategies.
The research team hopes that these unique, untapped NA dark side targets could influence the next generation of broadly protective vaccines against influenza. However, in the near future antibodies targeting the dark side could be combined with existing antivirals and antibody interventions to improve patient outcomes.