A new study from Instituto Gulbenkian de Ciência in Portugal has shown that malaria infection rates are significantly decreased in individuals with increases in particular antibodies derived from interactions with their microbiome.

Plasmodium falciparum/CDC
Plasmodium falciparum/CDC

Malaria is a mosquito-borne illness caused by the protozoa Plasmodium falciparum.  The disease is endemic worldwide, infecting approximately 219 million people and killing 660,000 per year.  Researchers have long known that certain pathologies confer resistance to the deadly form of malaria, instead causing chronic cold-like symptoms.  For example, individuals with sickle cell anemia have deformed red blood cells, which prevents the protozoa from completing its life cycle, allowing someone to become infected but not develop full-blown disease.

A common goal is to use this resistance as a means of developing a vaccine, but clinical trials have been met with little or no success.  Now, the Portuguese researchers have demonstrated that the human microbiome can provide some resistance by forcing the body to develop antibodies to the carbohydrate Gal-α-1-3Galb1-4GlcNAc-R (α-gal).  This carbohydrate decorates the surface of many microbes, as well as protozoa, but has been evolutionarily removed from human cells.

The researchers first showed that in Mali, where malaria is endemic, individuals with higher levels of anti-α-gal antibodies had a much lower chance of contracting malaria.  The team then moved to a mouse model, where they inoculated germ-free mice (mice lacking a microbiome) with two strains of Escherichia coli: one that produced α-gal, and one that did not.  As expected, mice with α-gal-producing E. coli produced anti-α-gal antibodies, with no harm to the mice.  When challenged with Plasmodium berghei (a close relative of P. falciparum), mice producing anti-α-gal antibodies were half as likely to develop malaria than their non-α-gal controls.

To determine whether it was the antibodies that were producing the effect and not the microbes, the researchers performed two experiments.  First, they produced a knockout mouse strain that was unable to produce antibodies, and showed that even when inoculated with α-gal-producing E. coli the mice still developed malaria.  Second, the researchers injected germ-free mice with a synthetic α-gal, and showed that even without α-gal -producing E. coli the mice still survived.  This proves that antibody production is necessary for resistance to malaria.

The ultimate goal of this research is to help produce a better vaccine.  “We think that by putting α-gal together with [a vaccine] protocol, we can increase by 10- to 100-fold the potency of this vaccination protocol,” said corresponding author Miguel Soares. “That remains to be tested . . . but what a wonderful thing, if this was true.”