West African Fulani exhibit a strikingly different susceptibility to malaria compared to sympatric Mossi, Rimaibé and Dogon. Despite being exposed to similar epidemiological contexts and parasite inoculation rates, Fulani show clear differences in their response to malaria at parasitological, clinical, and immunological level. Traditional genetic malaria protective factors such as hemoglobin (Hb) S, HbC, G6PD deficiency, or HLA class I and II, are not involved in this protection. Several experimental observations point to a hyper immune reactivity of Fulani, perhaps as a consequence of a functional deficit of T regulatory cells in this ethnic group. Micro RNAs (miRNAs) are well known post-transcriptional regulators of gene expression which, as part of complex regulatory networks, participate to practically every aspect of cell life, from cell growth and differentiation to development and immunity. Micro RNAs are found not only in cells and tissues but also in animal body fluids (e.g. serum, urine, saliva, cerebrospinal fluid); here they circulate either associated to Argonaute proteins or within extracellular vesicles (microvesicles and exosomes), which protect them from degradation and appear to play roles in cell-cell communication. Moreover, growing evidence suggest that they are important modulators of development and function in the immune system. With the aim to shed some light on the molecular basis of the different susceptibility to malaria exhibited by Fulani and Mossi from Burkina Faso, we propose here to analyze and characterize the miRNA populations of individuals from these two ethnic groups and verify if differences in miRNA repertoires from serum or peripheral blood mononuclear cells may help explain their different resistance to malaria.
This project has at least two innovative aspects that may allow for a significant advancement of our current knowledge and understanding. The first has to do with the genetic and/or epigenetic factors which may contribute to protection against an infectious disease of great relevance to human health as malaria. Understanding the mechanisms underlying Fulani resistance to malaria is not only an interesting scientific question and a challenge, but may open novel perspectives and identify novel targets to better control this devastating disease.
The second certainly relies on the emerging functions of exosomal miRNAs. While both the role and the mechanism of action of cellular miRNAs are well known, the possible contribution of extracellular and/or exosomal miRNAs to cell-cell communication is not well established. In fact, if from one side pretty convincing experimental proofs of exosome involvement in cell-cell communication are available, on the other side their role is still controversial. The comparative analysis of the miRNA repertoires (from plasma exosomes and from PBMCs) amongst ethnic groups with different genetic background and response to malaria represents a completely novel experimental approach which may provide a novel exciting view of the immune regulatory mechanisms underlying a protective response to P. falciparum parasites.