Malaria parasites hijack a part of the human immune response called the complement system to invade red blood cells, according to new study published in EBioMedicine. This finding could help in the design, development and testing of more effective anti-malaria vaccines.

The complement system

The complement system, part of the innate immune system, consists of a number of small proteins found in the blood. These proteins are activated in response to an infection, triggering an enzyme cascade that enhances (or complements) the ability of antibodies to fight invading pathogens.

Previous research had shown that other infectious disease pathogens can make use of the complement system to evade the immune response, but the process had never been demonstrated in malaria. Therefore, a team of researchers, led by Dr. José A. Stoute of Penn State College of Medicine, set out to see whether complement activation enhances malaria’s ability to invade red blood cells. As part of their research, the team utilized Kerafast’s Complement C3 [1H8] Antibody, which recognizes several proteins involved in the complement system cascade: human C3, C3b, iC3b and C3d.

Invading red blood cells

The researchers looked specifically at the malaria parasite Plasmodium falciparum. It is one of five Plasmodium species that can infect humans, but P. falciparum is the most deadly. They first demonstrated in vitro that anti-malaria antibodies actually enhanced P. falciparum growth in the presence of complement proteins. When the complement proteins were not present, the malaria parasites did not grow as effectively. They then tested the idea in a mouse model. Mice lacking a specific complement system protein had lower levels of the mouse malaria parasite P. berghei in their red blood cells after being infected.

The question is: how do malaria parasites use a host’s complement system to their own benefit? The answer is not yet clear, but the research team outlined their theory behind the process. Red blood cell surfaces have complement receptors, which protect the cells from self-attack from complement proteins. The researchers witnessed the malaria parasite coming in contact with complement receptors as it was trying to invade the red blood cells.

“We suspect that when complement gets activated by antibodies, the malaria parasite gets coated with complement proteins that normally would kill it,” Dr. Stoute said in a press release. “Instead, complement proteins allow the parasite to bind to complement receptors on the red blood cell. That allows the parasite to actually stick to the cell and then proceed to get inside it.”

A better malaria vaccine?

The researchers hope their findings could eventually lead to a more effective malaria vaccine. The disease kills close to one million people worldwide each year, mostly children under five in sub-Saharan Africa. Only one vaccine has been licensed to date, and it’s not 100 percent effective against the disease. In addition, attempts to develop a malaria vaccine that blocks red blood cell invasion (the stage at which clinical symptoms of malaria arise) have so far failed. Though anti-malaria antibodies have worked to block red blood cell invasion in vitro, these studies have not translated to efficacy in humans.

The new study suggests the complement system should be taken into account when designing new malaria vaccines and treatments. For example, one approach might be to introduce antibodies that are less likely to trigger the complement system. Complement inhibitors might also be used to treat people with severe malaria.

“Our results contradict the dogma of what the complement system does, and will likely be subject to a lot of scrutiny,” Dr. Stoute said. “Our findings suggest that development of an effective malaria vaccine that blocks red blood cell invasion is a more difficult task than initially thought. At the same time, we are now in a better position. By learning the malaria parasite’s tricks, we may be able to bypass them.”

Do you work in this area of research? Check out our related reagents for infectious disease and immunology studies, including:

• Complement antibodies from the University of Virginia and University Medical Center Göttingen

• Malaria-vector Anopheles gambiae antibodies from the University of Georgia