Protection from malaria in the Fulani ethnic group of West Africa involves reduced levels of A-to-I RNA editing by ADAR1 (QuinADAR1)

Every year, there are an estimated over 200 million cases of malaria worldwide. Malaria is caused by infection with the protozoan parasite Plasmodium, which are spread by the bite of a malaria-infected Anopheles mosquito. Despite a concerted international effort to combat the disease, malaria still causes approximately half a million deaths every year, the vast majority of which are young children with Plasmodium falciparum infection in sub-Saharan Africa. An acknowledged hurdle in the development of new strategies for the treatment and prevention of malaria is our limited understanding of the biology of Plasmodium infection and its complex interaction with the human host.

Previous investigations have shown what mediates an effective human immune response to infection with P. falciparum malaria. Specifically, through studying the Fulani ethnic group of West Africa, who are relatively resistant to malaria infection. Since the first report of the different response of Fulani to P. falciparum in 1996, populations of Fulani from Mali to as far east as Sudan have consistently been reported to have fewer symptomatic cases of malaria, lower P. falciparum infection rates, and lower P. falciparum density in infected individuals. The basis of the Fulani protection from malaria has never been established. However, a pilot study was conducted which suggested that reduced levels of adenosine-to-inosine (A-to-I) editing of RNA following P. falciparum infection can drive a more effective innate immune response in the Fulani.

A key role of A-to-I editing of RNA is the regulation of innate immunity via the RIG-I like receptor (RLR) antiviral response pathway. The conversion of adenosine (A) to inosine (I) by hydrolytic deamination is the most common RNA base modification in humans. A-to-I modification is catalysed by two adenosine deaminases acting on RNAs (ADARs), ADAR1 and ADAR2, which act upon double stranded RNAs as substrates. A-to-I edited sites are widespread, with millions of editing sites identified in the human transcriptome. During infection, RLR family receptors Retinoic acid-inducible gene I (RIG-I) and Melanoma differentiation-associated gene 5 (MDA5) detect viral RNA and signal via MAVS to activate the antiviral immune response, including activation of type I and type III interferons (IFNs) and pro-inflammatory cytokines. The activation of the RLR pathway by viral or other ‘non-self’ RNAs, but not RNA of the human cell (‘self’ RNA) can be regulated by A-to-I editing of ‘self’ RNA by ADAR1. In the absence of ADAR1, unedited ‘self’ RNA can be recognised as ‘non-self’ and activate the RLR pathway, upregulating innate immune responses.

Project details

Basic Science
Immunology

Jun 2019 — Nov 2021

$166,798

Czechia