Access denied: Stopping rabies virus from entering cells

Structural insights pave the way for development of new vaccines and therapies against rabies

Rabies virus can cause fatal neurological disease when access to medication is scarce. Tackling this issue will require novel vaccines and therapies to be developed and the viral surface protein may be a suitable target for these interventions. This protein arranges in triplets, but the structure of this arrangement has not yet been determined and the interaction between this triplet and therapeutic agents remains to be characterised. In a recent publication in Cell Host & Microbe, a research team at the University of Oxford collaborated with the electron Bio-Imaging Centre (eBIC) at Diamond Light Source to solve the cryo-electron microscopy (cryo-EM) structure of the triplet in complex with two therapeutic agents. Building on this work, the scientists investigated the mechanism by which licensed therapies inhibit the viral protein. The structural insight gained from this work will allow for strategic development of new vaccines and therapies against the virus.

A growing medical concern with limited treatments

Rabid animals typically spread rabies virus to humans by biting and this can cause a lethal neurological infection. Despite the development of vaccines and therapeutics, over 60,000 people die each year from rabies. Most of these deaths occur in African and Southeast Asian countries, where the virus is endemic in animals and access to medical intervention is insufficient. There is a growing necessity to design accessible therapeutics in response. Currently, vaccines can prevent rabies, but multiple doses are often required to achieve protection. Exposed individuals can additionally be treated with antibodies — components of the immune system that detect and block specific microorganisms (e.g. bacteria or viruses). There is concern however that currently available antibodies may not be protective against new variants of the virus and additional antibodies need to be produced.

A dynamic viral protein drives virus entry into the cell

Vaccines and antibody therapies target a single protein on the surface of the rabies virus. This aptly named ‘fusion’ protein engages with cellular proteins and triggers fusion of the virus with the cell, allowing infection to begin. Fusion proteins come together in triplets and change shape to drive fusion. The triplets initially form an open tripod (i.e. in which the three ‘legs’ are splayed). To allow fusion, the legs then fold into a closed-tripod arrangement. The researchers purified the fusion protein as a triplet in the open-tripod arrangement to study its architecture and association with antibodies.

Read more on the Diamond website

Image: Graphical abstract from DOI: 10.1016/j.chom.2022.07.014

Credit: reused under the CC BY 2.0 license