Autoimmunity protects against malaria

Understanding the interaction between infectious disease and autoimmunity

Malaria is one of the world's leading infectious diseases. It leads to death in many children. Researchers at the Bernhard Nocht Institute for Tropical Medicine (BNITM), together with collaboration partners, have discovered that autoimmunity associates with protection against clinical malaria. The study shows that autoantibodies inhibit the growth of the malaria parasite and bind to proteins that are important for invasion of red blood cells. The study was recently published in the journal Immunity.

A microscopic image shows red blood cells, some of which are infested with malaria parasites.

Malaria has been around for at least a hundred thousand years. It has accompanied humans throughout their evolution. The single-celled malaria parasite Plasmodium falciparum causes the severe form of the disease, malaria tropica. In 2022, an estimated 250 million people contracted malaria, the majority of them malaria tropica; 600,000 of them died, most of them children. 

Autoimmunity protects against malaria

Autoimmunity is an immune response directed against the body's own structures and can lead to autoimmune diseases such as rheumatism - autoantibodies bind to the body's own tissues. There is a known link between autoimmunity and malaria: Many previous studies have found autoantibodies in malaria patients. What these studies have in common is that the autoantibodies were measured after the malaria infection. 

Dr Christine Hopp: a researcher with blonde hair tied back, a dark blue blouse and a white and beige mesh jumper.
Dr Christine Hopp   ©BNITM | Dino Schachten

“It was known that malaria disease triggers the formation of autoantibodies,” says Dr Christine Hopp, author of the study and head of a laboratory group at the BNITM. “We wanted to test whether autoantibodies detectable before malaria in humans protect against febrile malaria.”

Hopp started the study while she was a postdoctoral fellow at the National Institute of Allergy and Infectious Diseases in the US. Colleagues at the Malaria Research and Training Center in Bamako, Mali, conducted the cohort study in Mali.

The researchers measured the levels of autoantibodies in 602 healthy children and adults in Mali before the malaria season and observed which of these people developed malaria in the following months. They found that people with high levels of autoantibodies had a 40% lower risk of developing a febrile malaria infection. The research team used statistical methods to check that other factors, such as age, did not distort the results. "It is the autoantibodies that are associated with the protection against febrile malaria infection," concludes Hopp.

Left: Fluorescence staining of autoantibodies. Right: Kaplan-Meier plot showing the probability of not contracting malaria.
Left: Analysis of blood plasma samples from the 602 subjects for autoantibodies. The intensity of the immunofluorescence indicates the amount of autoantibodies present: ANA- = blood plasma with no autoantibodies, ANA+ = blood plasma with few autoantibodies, ANA++ = blood plasma with a high level of autoantibodies. (ANA = antinuclear antibodies; the test was originally known as the antinuclear antibody test because it was developped to detect autoantibodies directed against nuclear structures. However, the test also detects autoantibodies against other cellular structures). Right: The Kaplan-Meier plot shows that people with high levels of autoantibodies (green line) are less likely to experience febrile malaria than people with low levels (yellow line) or no autoantibodies (red line).   Image credit: Immunity Cell Press | Hagadorn et al. 2024

Autoantibodies inhibit the growth of the malaria parasite and bind to proteins that are key for parasite invasion of red blood cells

Hopp and her collaborators also carried out experiments with parasite cultures to investigate the mechanism by which autoantibodies can protect against infection with the malaria parasite Plasmodium falciparum. They cultured red blood cells with the parasite. The parasite enters the blood cells, matures, multiplies, the blood cells burst and the newly formed parasites infect other red blood cells. When the scientists added autoantibodies, the parasites grew less. But why? The researchers showed that the autoantibodies bind to the parasites in the infected blood cells. To find out more about where the autoantibodies bind to the parasite, they carried out binding studies. The autoantibodies bound to some of the parasite's proteins that are important for entering the blood cell.

Crucial to the cell culture experiments and binding studies was that Hopp and her colleagues had developed a method to isolate the autoantibodies from the other antibodies in the blood plasma samples of the volunteers.

The fluorescence image shows the malaria parasite after attacking red blood cells.
The malaria parasite Plasmodium falciparum has infected red blood cells. The figure shows the malaria parasite at an early stage of development (trophozoite, top row) and at a later stage (schizont, bottom row). Column 1: Green fluorescent staining of the malaria parasite. The principle used to visualise the parasite is as follows: Autoantibodies (AAbs) bind to the parasite and fluorescently labelled secondary antibodies (green) bind to the autoantibodies, making them visible. Column 2: Pink fluorescent staining of red blood cells. Column 3: Combination of the images from columns 1 and 2 and staining of the malaria parasite DNA with a blue fluorescent dye. The multinucleate stage of the parasite is clearly visible in the bottom row. Column 4: Light microscope image of the motifs from columns 1 to 3.   Image credit: Immunity Cell Press | Hagadorn et al. 2024

Selective pressure of malaria on human genes

"What is exciting about this study is that it gives us an insight into the co-evolution of humans and malaria," says Hopp. Our immune system is faced with the difficult task of recognising pathogens as foreign structures on the one hand, and the body's own tissues and molecules as endogenous structures on the other. If this differentiation is successful, an immune response will only occur against foreign structures such as pathogens. How do pathogens evade the immune response? One mechanism used by pathogens is to resemble the body's own structures in such a way that the body does not recognise them as foreign. This is known as molecular mimicry. It seems likely that in its long co-evolution with humans, the malaria parasite has become increasingly similar to the body's own structures. As a counter-evolution, our immune system has adapted: It allows for more autoimmunity, because in this way it is able to provide a better immune response targeting the parasite. 

African Americans in the US are more susceptible to autoimmune diseases than people of European descent. “Our new data suggest that this higher susceptibility to autoimmune disease may have arisen long ago in Africa, because there is a survival advantage to malaria when there is a propensity for autoimmunity. Our results suggest that malaria may have been a strong driver for the emergence of autoimmunity,” explains Hopp.  

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