Posted: 25 September 2024
In a first-of-its-kind study, an international team of researchers has discovered how specific antibodies in young children protect against cerebral malaria, a life-threatening condition caused by the Plasmodium falciparum parasite, paving the way for improved, targeted treatments for this disease.
In collaboration with colleagues from Malawi, Denmark, Japan and the US, researchers from the Doherty Institute conducted detailed antibody profiling, sometimes called systems serology, to measure antibody responses to malaria in young Malawian children aged six months to 12 years. They compared responses in children with milder forms of malaria to those of children who presented with coma, a condition called cerebral malaria.
Malaria is caused by five species of Plasmodia, with the Plasmodium falciparum parasite causing the majority of malaria cases, including severe and fatal cases.
While antibodies play a vital role in defending against severe malaria, researchers have, until now, had a limited understanding of the types of antibodies that offer protection. This is the first time antibodies that interact with white blood cells and bind antibody helper molecules (collectively called complement), have been shown to help protect against life-threatening cerebral malaria.
The University of Melbourne’s Dr Isobel Walker, Research Fellow at the Doherty Institute and first author of the study, published in BMC Medicine, said they measured antibody responses to 39 variations of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a type of protein expressed on the surface of infected red blood cells that plays a key role in the malaria parasite’s ability to stick to blood vessels and contributes to its virulence.
“We found that using seven antibody responses to PfEMP1 proteins, we accurately distinguished cerebral malaria and uncomplicated malaria 87 per cent of the time,” said Dr Walker.
“Additionally, antibodies from children with uncomplicated malaria were better at triggering neutrophil phagocytosis, a process by which these white blood cells clear the malaria-infected red blood cells. The weaker response in cerebral malaria may help explain why these children had developed this more severe condition.”
Each year there are over 200 million cases of malaria, and over half a million deaths, and cerebral malaria is responsible for many of these deaths, which mostly occur in children under the age of five. Cerebral malaria is often accompanied by confusion, seizures, jaundice, abnormal bleeding and difficulties in breathing. Left untreated, this can result in death within 24 hours.
According to the World Health Organization (WHO), the African region carries a disproportionately high share of the global malaria burden, accounting for 94 per cent of malaria cases and 95 per cent of malaria deaths.
While studying the PfEMP1 protein, the researchers analysed not only the number of antibodies, but also their types and functions, such as how effectively they bind to immune receptors and trigger immune responses.
University of Melbourne’s Professor Stephen Rogerson, Head of the Malaria Laboratory at the Doherty Institute, said the systems serology approach proved a powerful tool to identify important aspects of antibody responses that help protect young children from life-threatening cerebral malaria.
“Antibodies have a head and a tail. The right head can bind to the dangerous malaria protein. The right tail can bring in white blood cells and other proteins to clear the malaria parasite,” said Professor Rogerson.
“We’ve had little idea of what kind of antibodies might protect children from severe malaria. By identifying the key targets and functions of antibodies that may protect against cerebral malaria, we can develop new ways of treating or preventing this leading cause of death in young children.”
The next step for researchers is to leverage this insight to identify potential vaccine candidates or treatments that stimulate the production of these specific antibodies and strengthen the body’s natural immune defences against life-threatening cerebral malaria.
