Malaria, particularly in its severe forms, remains a global health and economic burden. It causes the death of more than 600,000 people each year, most of them African children under the age of five. In a new study, published in the journal Nature, Researchers from EMBL Barcelona, ​​the University of Texas, the University of Copenhagen and the Scripps Research Institute have discovered human antibodies capable of recognizing and targeting some of the proteins responsible for severe malaria. This advance could pave the way for future vaccines or anti-malaria treatments.

Severe malaria is caused by the parasite Plasmodium falciparum, which infects and modifies red blood cells. These changes can cause red blood cells to stick to the walls of tiny blood vessels in the brain. This leads to impaired blood circulation and blockage of small blood vessels, which causes swelling of the brain and can progress to cerebral malaria.

The blockage of blood flow is mainly due to a family of about 60 virulent proteins, called PfEMP1, present on the surface of infected red blood cells. Certain types of PfEMP1 proteins can attach to another human protein called EPCR on the surface of cells lining blood vessels. This interaction damages blood vessels and is closely linked to the development of life-threatening complications.

Researchers knew that as African children grow up, they gradually develop immunity and that adolescents and adults rarely suffer life-threatening complications. This protection was thought to be mediated by antibodies targeting PfEMP1.

PfEMP1 is a highly variable protein and has long been considered a technically challenging vaccine target. A long-standing question therefore is whether the immune system can generate antibodies (proteins that recognize and neutralize specific pathogens) that can target the wide variety of circulating PfEMP1 types.

We were hesitant about being able to identify a single antibody capable of recognizing them all. And it turned out that our improved immunoscreening methods developed at the University of Texas quickly identified two examples of broadly effective human antibodies against different versions of the PfEMP1 protein. They both targeted a part of the protein known as CIDRα1 that interacts with the EPCR receptor. »

Maria Bernabeu, co-lead author of the paper and group leader at EMBL Barcelona

The team then had to test whether these antibodies could also successfully block EPCR binding in living blood vessels. In most diseases this could have been tested in animal models. However, for malaria this is not possible because the virulent proteins of the parasites that infect mice are very different from those of their human counterparts.

Researchers have developed an innovative approach to overcome this challenge. They developed a way to grow a network of human blood vessels in the laboratory and pass human blood infected with living parasites through the vessels, thereby reconstructing the disease in a dish. These experiments demonstrated that the antibodies were able to prevent the accumulation of infected cells, suggesting that they could help stop the blockage that leads to severe malaria symptoms.

“We used our organ-on-a-chip technology to recreate brain microvessels in 3D, which we then infected with malaria parasites,” said Viola Introini, a Marie-Skłodowska Curie postdoctoral fellow in the Maria Bernabeu group at the ‘EMBL Barcelona and co-first author. of work. “We introduced both antibodies into the vasculature and were impressed by how they prevented infected blood cells from sticking to the vessels. It was striking to see the inhibition readily apparent to the naked eye.”

Structural and immunological analysis by collaborators at the University of Copenhagen and the Scripps Research Institute revealed that these antibodies prevent parasite binding through a similar mechanism – by recognizing three highly conserved amino acids on CIDRα1. These broadly reactive antibodies likely represent a common mechanism of acquired immunity against severe malaria and offer new insights for the design of a PfEMP1-based vaccine or treatment targeting severe malaria.

“This study opens the door to targeting new ways to protect people from severe malaria, such as a vaccine or other treatments,” Bernabeu said. “It’s thanks to the international and interdisciplinary collaboration that is essential to understanding diseases like malaria. Our collaborators come from all over the world and study malaria from different perspectives. We must continue to work together to tackle big challenges like this -this.”

She added: “At EMBL Barcelona we believe that tissue engineering and organ-on-a-chip culture allow us to study diseases with much greater complexity and detail, as well as provide platforms useful for screening candidate vaccines. »