Malaria, one of the deadliest infectious diseases on the planet, has had a profound impact on humanity throughout history. This disease has even left its mark in our DNA: Many scientists believe it has had a strong selective pressure on the human genome over time. Because malaria is often fatal in children, babies born with some degree of resistance to the parasite that causes malaria have a better likelihood of growing up and passing those traits along to their own children. Unfortunately, some of these traits may come at a price: For more than 50 years, scientists have documented that malaria infection is associated with high levels of autoantibodies—antibodies that recognize and attack the person’s own tissues and are associated with autoimmune disorders.

To investigate the link between autoantibodies and malaria immunity, NIAID researchers, along with their colleagues, have studied the molecular mechanisms of these malaria defense systems. Their findings, recently published in Immunity, reveal the associations between malaria, human resistance to it, and autoantibodies that are linked to certain autoimmune disorders—specifically, systemic lupus erythematosus (SLE).

The researchers began by examining a collection of blood samples collected during a longitudinal study of 602 people, aged three months to 25 years, in the West African country of Mali. Malaria transmission is highly seasonal in Mali: the parasite which causes malaria, Plasmodium falciparum, is transmitted by mosquitoes, which need certain conditions to reproduce. During the dry season, which ends in May, malaria transmission rates are low. The researchers tested for autoantibodies in blood samples that were collected in May and then linked this with whether the participant had symptomatic malaria that needed treatment during the ensuing malaria season.

Participants who had very high levels of autoantibodies had a 41 percent lower risk of getting sick with malaria than people who had low levels of autoantibodies. To investigate how autoantibodies might protect from malaria, the researchers took blood samples with high levels of autoantibodies and isolated the autoantibodies. They then exposed malaria parasites to the autoantibodies in the laboratory and found that parasite growth was inhibited. The autoantibodies bound to proteins that the parasite uses to invade human red blood cells. The researchers believe that something similar may have happened to the participants of this study—their autoantibodies reduced the parasite’s ability to invade and grow in their blood cells, increasing their chances of remaining free of malaria symptoms.

Although this adaptation seems beneficial, it may come with a catch. Very similar autoantibodies can be found in the blood of people with SLE. This chronic autoimmune disorder can affect almost any organ system, but it often manifests as a rash, joint pain, and persistent fatigue. In its worst forms, it can be debilitating. While the causes of SLE are still unknown, it does appear to have a genetic component—for example, in the U.S., SLE is more common in some ethnic groups than others, including people with African ancestry. However, for unclear reasons, SLE and other autoimmune disorders are less common in Africa, suggesting that other factors alter the immune system to decrease the risk of autoimmune disorders there. Participants in the Mali study with high levels of autoantibodies had no symptoms of SLE or other autoimmune disorders.

When the researchers tested autoantibodies from people in the United States with SLE, they reacted to malaria parasites similar to the autoantibodies from the Malian study participants. These findings suggest that the overactive immune response that contributes to SLE may have evolved to defend against malaria. Even though many people with SLE today will never encounter a malaria-carrying mosquito, they still produce the antibodies that may have helped their ancestors survive malaria.

Reference:

Hagadorn, K et al. Autoantibodies inhibit Plasmodium falciparum growth and are associated with protection from clinical malaria. Immunity. DOI: https://doi.org/10.1016/j.immuni.2024.05.024 (2024)
 

NIAID Raises Awareness to Malaria-like Diseases in W. Africa

Dengue, Zika, Chikungunya Viruses in Mali; Disease Likely Misdiagnosed

NIAID scientists and colleagues have identified dengue, Zika and chikungunya viruses in the West African country of Mali, where health care providers likely misdiagnose patients with illness from those viruses due to unavailable diagnostic tools. Because malaria is the most common fever-causing illness in rural sub-Saharan Africa, most medical workers presume patients with a fever have malaria. The primary cause of all four infectious diseases is a mosquito bite.

Records from the Malian Health Information System show that about one-third of all patient visits to health care facilities are related to malaria, with 2.37 million clinical cases.

A new study from NIAID’s Rocky Mountain Laboratories and the University of Sciences, Techniques and Technologies in Mali aims to help spread information to medical workers about the existence of the additional viral diseases. Ideally, circulating the information will help them obtain the necessary diagnostics.

The study, published in The American Journal of Tropical Medicine and Hygiene, involved 600 residents, 200 from each of the southern Malian communities of Soromba, Bamba and Banzana. The scientists detected antibodies to dengue virus in the blood of 77.2% of the residents tested; to Zika virus in 31.2%, and to chikungunya virus in 25.8%. They detected at least one of the three viruses in 84.9% of participants, meaning just 15.1% tested negative to any of the three viruses.

Evidence of the parasites that cause malaria was found in 44.5% of those tested. Unlike malaria, however, where most cases are found in children under age 14, residents over age 50 were most likely to have been exposed to dengue, Zika or chikungunya viruses. 

“Despite the high exposure risk to dengue virus in southern Mali, dengue fever cases have rarely been reported,” the researchers write. “This is likely due to the lack of diagnostic testing and the biased clinical focus on malaria in the region. Awareness of dengue virus as a cause of febrile illness needs to be urgently established in medical communities as an important public health measure.”

The scientists are hoping data from a more in-depth clinical study that just ended will provide additional details about the prevalence of these viruses in Mali. They also are planning to examine patients who have undiagnosed fevers to establish infection rates.

NIAID scientists are investigating dengue, Zika and chikungunya viruses to try and develop preventive and therapeutic treatment options, none of which exist.

Reference: S Bane, et al. Seroprevalence of Arboviruses in a Malaria Hyperendemic Area in Southern Mali. The American Journal of Tropical Medicine and Hygiene DOI: 10.4269/ajtmh.23-0803 (2024).

For years, malaria vaccine developers have focused on thwarting a key moment in the malaria parasite’s life cycle: when two parasite proteins, AMA1 and RON2L, combine to form a complex that anchors the parasite to a red blood cell and eases its passage into the cell interior. Quite sensibly, researchers developed candidate vaccines that elicit antibodies capable of blocking the crucial attachment. However, because AMA1’s make-up varies widely among different parasite strains, any vaccine based on a single strain’s AMA1 cannot protect against other parasite strains and thus has limited usefulness in malaria-endemic countries. Experimental malaria vaccines have also been made by mixing AMA1 and RON2L proteins. While these do elicit more strain-transcending antibodies than AMA1-only vaccines, they are difficult to manufacture and simple mixtures of AMA1 and RON2L in vaccines do not form the kind of stable protein complex seen in nature.

Now, researchers in NIAID’s Laboratory of Malaria Immunology and Vaccinology have used structural information about the two parasite proteins along with mechanistic information about the interaction between AMA1 and RON2L to design and build an entirely novel immunogen (the component of a vaccine that elicits an immune response). When tested in rats, their “structure-based design 1” (SBD1) immunogen vaccine performed better than any AMA1 or AMA1-RON2L vaccine. It also upends the conventional wisdom that successful vaccines must elicit receptor-blocking antibodies, notes Niraj H. Tolia, Ph.D., who led the research team.

The SBD1 immunogen does not exist in nature, explains Dr. Tolia. Rather, it consists of AMA-1 that the team altered by rearranging its amino acid sequence in a way that they predicted would work well as a vaccine. Once altered, the scientists linked RON2L to a position in their immunogen to recreate the two protein AMA1-RON2L complex. The team analyzed the structure of the designed immunogen using X-ray crystallography and determined that it closely mimicked that of naturally occurring AMA1-RON2L complex. However, SBD1 has a number of advantages over a simple mixture of two component proteins, Dr. Tolia explains. For instance, it is highly stable once injected, is easy to manufacture in large quantities and consistently takes the desired, immune-stimulating shape.

In rats, SBD1 vaccine elicited significantly more potent strain-transcending antibodies than either AMA1 alone or an AMA1-RON2L complex vaccine. The ability to provide protection from multiple parasite strains is highly desirable for any malaria vaccine. Most surprisingly, Dr. Tolia says, the SBD1 vaccine provided this strain-transcending protection even though it generated no antibodies whatsoever that were aimed at blocking AMA1 from binding to RON2L and initiating attachment to the red blood cell. Instead, it appears SBD1 elicits high quality antibodies that inhibit parasite growth by targeting parts of the parasite’s proteins that lie outside of RON2L binding site and operate independently of receptor blockade, explains Dr. Tolia.

Together, the team’s observations about SBD1 make it an appealing candidate for further studies in animals and perhaps ultimately in human trials, he adds. Furthermore, other parasites, including those that cause the human diseases toxoplasmosis and babesiosis and one that causes disease in cattle and dogs, use their own forms of AMA1 protein to invade host cells. Thus, insights gained in this recent work may be applicable to the design of vaccines against those parasites as well.

Reference: PN Patel et al. Structure-based design of a strain transcending AMA1-RON2L malaria vaccine. Nature Communications. DOI: 10.1038/s41467-023-40878-7 (2023).