To catch a killer: DNA fingerprinting reveals how malaria hides from our immune system
DNA fingerprinting has revealed how the malaria parasite shuffles genes to create different strains and hide from our immune system. This trick allows the parasite to remain undetected and re-infect the same people, much like the flu. An international team of scientists, including Dr Yael Artzy-Randrup of the UvA Institute for Biodiversity and Ecosystem Dynamics, have published this research in the journal PNAS on 2 May 2017.
A study involving more than 600 children living in a small village in southeast Gabon, near the border with the Republic of Congo, found that each infected child in one African village had a different strain of the malaria parasite, and a distinctly different set of the up to 60 genes that the human immune system focuses on to detect and control this infection.
The findings help explain why people can’t develop immunity to malaria and indicate that control programs should now focus on looking at the impact not just on the number of infections but the structure of diverse strains of the parasite.
‘The study began with collection of blood from 641 children, aged 1 to 12 years, living in the small village of Bakoumba, Gabon. Children in the area are frequently exposed to malaria, receiving about 100 bites from infected mosquitos each year, said Prof. Karen Day, study author and Professor of Population Science and Dean of Science, University of Melbourne.
‘We produced a genetic fingerprint of malaria parasites from small amounts of blood based on what are called var or variant antigen genes. These genes encode proteins that coat the surface of the red blood cells when infected by a parasite, and are important because they allow the parasite to disguise itself from the human immune system,’ added Prof. Day.
Variant antigen gene
The malaria parasite is a single-celled microorganism (known as a Plasmodium) that infects red blood cells and is transferred from human to human via mosquitoes. Every parasite has approximately 60 of these var genes and can switch between them.
‘Looking down the microscope you would think all of the infections look the same, but when we did the genetic fingerprinting with this variant antigen gene system, we could see that every child had a different parasite fingerprint, and importantly, each fingerprint was highly unrelated to all other fingerprints.
Our results show that the parasite has evolved this enormous diversity with limited overlap between the sets of var genes. This structure allows each parasite to look different to the immune system, and provides the possibility for the malaria parasite to keep re-infecting the same people because it exists as different ‘strains’ that can persist for many months.'
Currently however, the theory of malaria control is based on malaria having no diversity and being more like measles. You contract measles once and have life long immunity, whereas you can get malaria or the flu many times because there are multiple strains circulating.
'Malaria is more similar to flu in that humans can be infected multiple times by different malaria parasite variants', Dr Artzy-Randrup of UvA explains. 'However, in contrast to the flu, the situation with malaria is much much more complex. With malaria, at any given point of time there is a high diversity of variants coexisting even in very small human populations, while in flu, variants usually replace each other, and people will only be infected by one variant at a time', Dr Artzy-Randrup adds.
Computer analyses conducted by Dr Artzy-Randrup on the variation in these sets of genes shows how they might respond to control efforts with anti-malarial drugs. The non-random pattern has 'implications for the success of malaria-control programs,' the authors note. It supports the notion that a large number of strains of the disease, each characterized by a significantly different combination of surface-coat proteins, could result in many children remaining infected even after aggressive efforts to intervene, such as mass drug administration.
'This is an exciting time for bringing together quantitative analyses and deep sampling of biological systems in the field.' Says Prof. Mercedes Pascual, an Ecologist from the University of Chicago who is a member of the team.
The international team from the University of Melbourne, the University of Chicago and the University of Amsterdam are now var code fingerprinting and modelling malaria strains in larger human populations through time. ‘Ultimately, the question we all want to answer is, how can we defeat humanity’s most unrelenting enemy?’
Karen P. Day, et. al (2017). Evidence of strain structure in Plasmodium falciparum vargene repertoires in children from Gabon, West Africa. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.1613018114