Malaria integrative Analysis to Discover Biomarkers of Infection Outcome – MAD-BIO

Most of the half a million annual deaths by malaria are due to P. falciparum. This unicellular eukaryote parasite is transmitted by female Anopheles mosquitoes. Malaria symptoms may occur during the intra-erythrocytic part of the parasite life cycle. A P. falciparum infection can result in a wide range of outcomes, from asymptomatic (no visible sign of an infection), to uncomplicated or severe malaria and death. The heavy malaria burden, in terms of clinical cases and deaths, is only the tip of the iceberg. Indeed, on any given day, the vast majority of all P. falciparum infected carriers worldwide are asymptomatic. In Uganda, 84% of the human infectious reservoir consists of microscopically detected asymptomatic infections. These long-lasting chronic infections are key to the parasite survival in the dry season when there is no transmission. This reservoir is arguably the biggest challenge for malaria eradication, as clearing all infections includes treating carriers without clinical symptoms who are unlikely to seek treatment. In collaboration with Sandrine Nsango at the Centre Pasteur du Cameroun, in May and September 2021 we recruited a new cohort of 57 children from two schools near Yaoundé. In this new cohort in Cameroon, 8-10 years old children got infected with P. falciparum within 2 months, resulting in chronic infections (53%), short lasting infections (23%) or symptoms development (24 %) with immediate treatment.
The discrepancy in infection outcomes suggests a large diversity of parasite virulence and/or host susceptibility. The host-pathogen interaction is mediated at least partly by the parasite antigenic variation and the host immune response. To disentangle these two variables, the MAD-BIO project will sequence PBMCs and P. falciparum parasite transcriptomes at the single-cell level from the same blood samples collected before, during and after the infection. This unprecedented approach, in its longitudinal study design as well as its state-of-the art technology, will identify biomarkers predictive of the infection outcome and decipher the mechanisms of the parasite interacting with its natural host.
More specifically, the original design of our longitudinal study will address the following questions:
- Aim 1: Based on the host transcriptome of an uninfected individual, can the outcome of a future P. falciparum infection be predicted? Or is the presence/absence of symptoms best explained at the onset of the infection?
- Aim 2: What is the role of the parasite antigenic variation in the early stage of an infection in triggering the immune response? Does the parasite first express its most virulent antigens or is it dependent on host immunity? How does the parasite keep evading the immune system in a chronic infection?
- Aim 3: Do the parasite and host adapt their response against each other through transcription regulation?
To do, we have established and optimised novel protocols to analyse, for the first time, the parasite and host transcriptome in chronic P. falciparum infections.
The preliminary analyses that we carried out and validated ensure the project feasibility. MADBIO is a multidisciplinary project between three academic partners with synergistic competences in the field of malaria research. Together, our expertise covers all technical and scientific aspects of the project at the interfaces of health-biology: host and parasite genomics, immunology, and bioinformatics data integration.
In conclusion, our proposal is a rare effort to truly decipher the mechanisms of the host-pathogen interaction of P. falciparum in its natural host, fitting nicely within the "Immunology, Infectiology and Inflammation" axis. Most importantly, the discovery of host and parasite biomarkers of the outcome of an infection will put us in a position to identify and protect people most at risk, but also direct malaria elimination campaigns against long-lasting infections, the reservoir of P. falciparum.