AsianScientist (Jun. 25, 2015) – The crystal structure of a protein found in the midgut of malaria-transmitting mosquitoes has been solved to a resolution of 2.65-Å. These findings, published in Nature Structural & Molecular Biology, could aid the design of a new type of vaccine that aims to reduce malaria transmission instead of boosting host immunity.
Malaria is transmitted to humans by the bite of a mosquito infected with the Plasmodium parasite. Vaccinated individuals in malaria-endemic countries have been observed to produce antibodies to alanyl aminopeptidase N (AnAPN1), a protein in the Anopheles mosquito midgut that is thought to be a receptor for the parasite. Currently, the AnAPN1 protein is a leading candidate for a mosquito-based malaria transmission-blocking vaccine.
“This type of vaccine won’t boost people’s immunity to malaria, but instead it will provide a delayed benefit to the individual by protecting the entire community from parasite transmission,” explained Dr. Rhoel Dinglasan from the Malaria Research Institute at the Johns Hopkins Bloomberg School of Public Health.
“Ultimately it could lead to a reduced number of infected mosquitoes and the eventual elimination and eradication of the disease.”
When immunized individuals become infected with malaria parasites, both the anti-AnAPN1 antibodies and parasites are ingested by a mosquito during blood feeding. The antibodies block parasite development in the mosquito, breaking the cycle of transmission.
However, while AnAPN1 prompts people to make antibodies, only some of these antibodies are able to successfully block parasite transmission.
“This dilution of the overall antibody response to AnAPN1 is problematic. To further improve vaccine immunogenicity at the preclinical stage, we need to immuno-focus the antibody response to only the critical, ‘transmission-blocking’ regions of the protein,” he said.
An understanding of how AnAPN1 antibodies that are generated can block parasite transmission to mosquitoes and their binding region on AnAPN1 has remained elusive until now. Using the Australian Synchrotron, Dr. Natalie Borg’s team at Monash University was able to visualize the crystal structure of the AnAPN1 protein for the first time, providing valuable insights. Dinglasan’s team then provided the critical functional data to support the hypotheses generated by the AnAPN1 structure.
“The Australian Synchrotron was critical in providing detailed imaging of the structure of AnAPN1. In combination with other experimental data, the structure enabled us to pinpoint the binding site of AnAPN1 antibodies that can and can’t block parasite development,” Borg said.
“We now know much more about which parts of the AnAPN1 protein are involved in generating transmission-blocking antibodies and have a new hypothesis as to how they might work,” she said.
This discovery will fuel further work to understand what critical interaction the AnAPN1 transmission-blocking antibodies are blocking. It will also prompt the redesign of the AnAPN1 antigen to make it more effective.
The article can be found at: Atkinson et al. (2015) The Anopheles-Midgut APN1 Structure Reveals A New Malaria Transmission–Blocking Vaccine Epitope.
Source: Monash University; Photo: Shutterstock.
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