October 25, 2021

I, Science

The science magazine of Imperial College

The malaria parasite reshuffles its DNA to evade our immune systems

malaria picMalaria parasites have a cunning mechanism of hiding from the immune system of their human hosts: rapidly changing the proteins recognized by the hosts’ defences.

This evasion tactic, which is described in work published in PLoS Genetics, explains how the parasites manage to survive in infected hosts for such long periods of time, and may be the reason why we have yet to develop effective vaccines for malaria.

Researchers from the Wellcome Trust Sanger Institute in Cambridge, UK, found that the parasite Plasmodium falciparum, which accounts for most cases of malaria worldwide, rapidly increases the diversity of its 60 var genes through a process known as recombination – this is the swapping of information between different gene regions to generate new genes.

Lead author William Hamilton likened var genes to “decks of cards constantly being shuffled”. “The use of whole genome sequencing and the sheer number of samples we collected gave us a detailed picture of how the var gene repertoire changes continuously within red blood cells,” he added.

Unlike what was previously thought, this swap of genetic information does not happen while the parasite is in its mosquito host but, instead, while it resides within red blood cells in humans. This is the ‘asexual’ stage of the parasite’s life cycle. 

Var genes are key to immune evasion because they encode distinct forms of the protein PfEMP1, which is expressed on the surface of red blood cells and can therefore be recognized by the host’s defences. Previous work had shown that P. falciparum varies its expression of PfEMP1, causing what is known as antigenic variation, by expressing only one var gene at any time point and silencing the other 59 genes, which ensures that the parasite remains hidden from the immune system.

The researchers estimate that the recombination rates could give rise to millions of new var genes every two days in each infected host. According to the researchers, this means that throughout the course of an infection the parasite can accumulate a vast number of PfEMP1 variants, which would allow the selection of those that will be most effective at hiding it from the host’s defences.

“When you consider that 200 million people across the world are infected with malaria and each of them is harbouring parasites that are continually generating millions of antigenic variants, it becomes apparent why our fight against malaria is so challenging,” said Professor Dominic Kwiatkowski, head of the Malaria Programme at the Wellcome Trust Sanger Institute.

The researchers hope that a better understanding of this process might help us develop new strategies to target malaria parasites.