Researchers have found a weakness in the parasite's armor
Danish researchers, leading an international collaboration, have made an important discovery: antibodies that can target the malaria parasite's secret weapon and "Achilles' heel." The discovery, published in Nature, could pave the way for an effective vaccine.
The most severe type of malaria is deadly; the parasite hijacks red blood cells and attaches itself to the inner surface of the body’s smallest blood vessels, in order to avoid ending up in the spleen, where it would otherwise be removed. This attachment requires the help of special binding proteins on the surface of the blood cells. This is the parasites’ secret weapon, but it turns out it’s also their Achilles' heel.
The parasite produces these binding proteins in approximately 60 variants, so it can choose among them like a master of disguise, evading the immune system and consequently taking 600,000 lives annually, with young children particularly at risk. Those who survive infection develop antibodies against the parasites, as the immune system gradually learns to recognize the parasite's many different binding proteins. This immunity is the foundation for this research breakthrough.
Researchers have debated for decades whether the immune system can develop a broad-spectrum antibody that can recognize all protein variants, or whether the parasite can constantly escape by displaying new variants. The answer to this question is crucial for the development of a vaccine, and the discussion has now taken a new turn.
It is fantastic that after so many years of speculation and discussions, we have finally shown that broad-spectrum antibodies exist, and at the same time found this Achilles' heel in the parasite's proteins, the existence of which we have hypothesised for the last twenty years.
Danish researchers, in collaboration with an international team of researchers, have discovered that people who are immune to malaria form antibodies that can recognise almost all variants of the proteins associated with severe disease. It turns out that the proteins have the same weak point; an obvious target for vaccine development efforts.
The discoveries have now been published in the journal Nature. One of the main authors is Professor of Molecular Parasitology Thomas Lavstsen from the Center for Translational Medicine and Parasitology (CMP) at the Department of Immunology and Microbiology, University of Copenhagen, KU.
"It is fantastic that after so many years of speculation and discussions, we have finally shown that broad-spectrum antibodies exist, and at the same time found this Achilles' heel in the parasite's proteins, the existence of which we have hypothesised for the last twenty years," Lavstsen says.
Having received an Ascending Investigator grant from the Lundbeck Foundation in 2020 to build on previous research results, Lavstsen is very pleased that he can now, together with the other researchers, deliver the article in Nature.
The parasite has adapted over millions of years
There are five species of malaria parasites that can infect humans, and the most severe malaria disease is caused by the parasite that Lavstsen and his team study, Plasmodium falciparum. The vast majority of Malaria-driven deaths and severe disease are caused by this species. Disease prognosis is particularly poor if the parasite becomes established in the brain and causes cerebral malaria, because fluid accumulation can result in seizures, comas and breathing abnormalities.
The disease hits young children hardest because their immune system has not learned to recognise the proteins on the parasite's surface. Each parasite has its own arsenal of binding proteins to choose from. They have the same function: to bind the infected red blood cells to specific receptors in the smallest blood vessels, but their molecular composition can vary. This is why they can escape the immune system, even though they are "exhibited" on the surface of the blood cells.
"The variation in the proteins has arisen because the parasites want to avoid being recognised by antibodies. The same thing is happening before our eyes now with the corona and influenza viruses," explains Thomas Lavstsen.
"The difference is just that the parasite has been here for millions of years, long before we became Homo sapiens, and they have already developed all conceivable variants."
International collaboration was vital to this breakthrough
Thomas Lavstsen and his co-author and colleague Louise Turner have researched malaria for over twenty years. The team from the University of Copenhagen and Rigshospitalet has previously demonstrated the connection between severe malaria symptoms and a specific section of the adhesive protein, the CIDRα1 domain, as well as the receptor to which the protein binds in the blood vessels, called EPCR. However, the new discovery of the broad-spectrum antibodies targeting CIDRα1 has required international expertise across disciplines.
Researchers from Tanzania and Uganda contributed with clinical studies and blood samples from people living in areas of high malaria prevalence, while researchers in the USA isolated immune cells and performed analyses of the antibody structures. In Spain, the new antibodies' effect on the parasites has been tested in advanced 3D models of the brain's blood vessels.
Four amino acids make all the difference
To fully understand the newly discovered weakness in the parasite's defenses, we need to look more closely at the make-up of the binding proteins and corresponding antibodies. Proteins consist of chains of amino acids that twist and fold into complex 3D structures. These structures are essential to a protein’s function, like the shape of a key to fit into a lock.
There are twenty different amino acids, so in a protein sequence, there can be thousands of amino acids in different combinations. Here, only a few of the amino acids in the overall sequence make all the difference - the CIDRα1 domain.
"We previously discovered that even though the parasite's binding proteins have vastly different sequences of amino acids, they form the same structure at the CIDRα1 domain, in order to be able to bind to the receptor EPCR."
Because the binding proteins sit on the surface of the cells, they are exposed to attack by the immune system, which is what happens when someone develops immunity to malaria.
Based on our new knowledge about antibodies, we will design a vaccine that will guide the immune system to react more specifically – ideally with long-lasting effects.
The new study describes two different broad-spectrum antibodies from separate adults from areas of high malaria prevalence, both of which block the binding between the parasite's adhesive protein and the receptor in the blood vessel walls.
"The antibodies are very different and come from different individuals, but we can see in their 3D structure that they bind different variants of the CIDRα1 binding proteins in exactly the same way. And most importantly – they bind to the same four amino acids, which are also the only ones the parasite has had to retain to maintain its binding to the receptor EPCR. It is molecularly quite fascinating."
The researchers believe that this may be a general mechanism for how broad-spectrum antibodies that can trigger immunity against severe malaria bind to the adhesive proteins.
The dream is a vaccine
The next step for Thomas Lavstsen and his team is to find out how common this type of antibody is, and how and how quickly it arises. The big dream is to develop an effective vaccine, and perhaps also a treatment against severe malaria.
"Even though there is an approved vaccine and more are on the way, we need to work on other strategies to increase effectiveness. Malaria is not like a virus – it is more complex. There are more stages and more ways to evade our immune system."
To match the parasite's evolutionary advantage and complexity, the researchers will use the latest technologies, including artificial intelligence, to design antigens. The same technology that has recently received special attention and recognition with the Nobel Prize in Chemistry.
"Based on our new knowledge about antibodies, we will design a vaccine that will guide the immune system to react more specifically – ideally with long-lasting effects."
The idea is to mimic the natural immunity that the adult population has developed in countries where malaria is endemic.
"Maybe it is optimistic to think that we can mimic nature. Maybe it is too complex. But we have to try," says Lavstsen.
"It is important to understand and try to take advantage of the strategy that has proven effective against malaria for millions of years. We cannot afford to ignore nature's solutions."
Malaria is one of the most serious diseases in the world, thought to have caused more deaths than any other infectious disease throughout history. Today, it is responsible for the deaths of more than 600,000 people each year, and ten times as many suffer from severe illness and complications. Most of the victims live in sub-Saharan Africa, but the disease is also found in Southeast Asia, South America, Central America, and the Caribbean.
Malaria is caused by parasites transmitted by mosquitoes. The parasites have one interest: to survive and spread as quickly as possible. They first invade cells in the liver, where they multiply, and eventually the cells burst, releasing the parasites into the bloodstream. Here they hijack red blood cells, multiply in them, and eat them from the inside until they also burst. This releases more parasites and waste products into the blood, causing symptoms such as fever, fatigue, and pain.
There are five species of parasites that can infect humans. Plasmodium falciparum is the most severe. Parasites of this species use a special technique to hide from the immune system. With a specific type of binding protein, they attach themselves to the smallest blood vessels and thus avoid the spleen, which otherwise removes infected blood cells.
The clustered blood cells trigger inflammation and can cause blood clots, leading to severe illness and death, especially if the parasite becomes established in the brain. In cerebral malaria, fluid accumulations can cause seizures and induce comas, while pressure on the brain’s respiratory centre can cause breathing to stop.
Lektor, Institut for Immunologi og Mikrobiologi, Københavns Universitet, har af Â鶹Éç fÃ¥et en Ascending Investigator...
