Malarial invasion protein yields structural clues for vaccine development
The structure of PfRH5: two views of the protein construct used for crystallisation studies, coloured as a rainbow from blue (N terminus) to red (C terminus) (Click to enlarge)
A group of Oxford researchers has revealed promising new findings about a protein necessary for invasion of red blood cells by malarial parasites.
The work from Dr Matt Higgins' lab in the department in collaboration with Dr Simon Draper at the Jenner Institute is published in Nature (1).
It describes the structure of Plasmodium falciparum RH5, the only malarial protein so far shown to be essential in the invasion process, and its interaction with host protein, basigin.
By targeting one of the best vaccine candidates for malaria, the work opens the door for the development of a new generation of vaccines against this deadly disease.
The RH5 protein belongs to one of two protein families that are important for the invasion process. Reticulocyte-binding protein homologue (RH) proteins are found in all Plasmodium species, but only RH5 from Plasmodium falciparum (PfRH5) has been shown to be essential in the invasion process in all tested strains.
'If you block other proteins that mediate host-parasite interactions, then the parasite switches to use another invasion pathway,' explains Dr Higgins. 'RH5 stands outside this and is essential for invasion by all parasite strains tested to date.'
Antibodies against PfRH5 or basigin, the erythrocyte surface protein it interacts with, efficiently block parasite invasion in vitro. And because PfRH5 is highly conserved, antibodies raised against one PfRH5 variant protect against parasites of all tested heterologous strains.
These unique features of PfRH5 have attracted the attention of researchers keen to develop a vaccine against the disease. Now, with the new findings from Dr Higgins and colleagues, they will be in a much stronger position to move ahead with this.
The structure of the PfRH5-basigin complex. The PfRH5 protein construct (yellow) is bound to basigin (blue) (Click to enlarge)
The paper presents the first crystal structure of a RH protein, using a protein construct of PfRH5 that is capable of binding basigin and is targeted by inhibitory antibodies. The group shows that PfRH5 adopts a novel fold, and by solving the structures of the protein in complex with basigin and two distinct inhibitory antibodies, also identifies the binding sites for these ligands at one tip.
The work, which was carried out largely by DPhil student Kate Wright, will help researchers understand which parts of PfRH5 are essential for its function and from this, design better immunogens for a vaccine.
Dr Higgins will continue his collaboration with Simon Draper to pursue this work. They will use rational immunogen design to explore aspects such as fragment stability, and establish if the fragments generate inhibitory antibodies. They will then test the immunogenicity of candidate immunogens in animals before progressing the lead candidate to clinical trials undertaken at the Jenner Institute in healthy adult volunteers.
'PfRH5 is currently the most promising malaria vaccine candidate, and a vaccine against it could be effective against many strains of the parasite,' adds Dr Higgins. 'We hope that the structure will guide us to design better and cheaper immunogens that are suitable for use in countries where malaria is present.'