Researchers have successfully produced antibodies that kill the parasite carried by the 'kissing bug' that causes the potentially deadly Chagas disease. The research is a vital step towards the development of the first effective vaccine.
Scientists from the University of Nottingham have revealed the three-dimensional structure of the TcPOP protein, which is passed to people's blood by the the parasite Trypanosoma cruzi, carried by the triatomine or "kissing bug." Their results have been published in Nature Communications.
Chagas disease (CD) is a ticking time-bomb for health systems around the world. It is one of the most neglected tropical diseases with an annual incidence of 56,000 cases and about 12,000 deaths. Seven million people are estimated to be infected worldwide, and a further 140 million individuals are at risk. Trypanosoma cruzi infections are life-long and around one third of chronically infected Chagas patients will develop severe life-threatening complications, including heart failure and sudden cardiac death, often decades after the initial infection.
The research team have isolated, produced and characterised the first parasite-blocking (neutralising) antibodies against two key T. cruzi proteins, TcPOP and Tc24 showing that in both cases neutralisation strikingly exceeds 95% and those antibodies target the parasite infective stage, which is key for vaccine development.
Using cutting-edge single-particle cryo-electron microscopy (cryo-EM), Dr Ivan Campeotto's group at the University of Nottingham captured TcPOP in both open and closed conformations. They discovered that the protein behaves like a microscopic "Pac-Man," degrading collagen on human cells to allow the parasite to invade and hide, thereby evading immune detection and enabling long-term persistence in the host.
"These results are a game-changer for Chagas research," said Dr Ivan Campeotto, lead researcher at the School of Biosciences.
TcPOP's small size made traditional structural methods challenging, but cryo-EM has finally allowed us to see it in action. These results were also corroborated by a plethora of structural biologic techniques in collaboration with many institutions. Understanding its mechanism opens new doors for disarming the parasite by targeting one of its key weapons.
To produce sufficient quantity of TcPOP for structural studies, Campeotto's team used large biofermenter in the School of Biosciences to express the protein in bacterial cells. This high purity protein was then used to immunise mice in collaboration with Prof. Lea Barfod (University of Copenhagen), leading to the isolation of potent antibodies which were tested in cell-invasion experiments in collaboration with Prof. John Kelly at the London School of Hygiene and Tropical medicine (LSHTM).
These antibodies kill (neutralise) parasites through two distinct mechanisms: a rapid "burst" effect within minutes, or a slower process (~30 min) by binding to the "feeding pocket", or flagellar pocket, likely disrupting nutrient uptake and leading to starvation.
Dr Campetto adds: "These are the first-ever neutralising antibodies identified against TcPOP and the first neutralising against this parasite, highlighting its potential as vaccine candidate to stimulate natural immunity in humans, or as a source for direct therapeutic antibodies to threat or prevent infections.
"Additionally, since TcPOP is secreted into the bloodstream, these antibodies hold potential for diagnostic applications, particularly in detecting congenital transmission from mother to foetus, a major route of infection that affects thousands of newborn annually. This is something we plan to explore further in future studies."
