Multi-Omics Analysis of Host-Parasite Interactions in Plasmodium falciparum Malaria

Abstract

Host responses in Plasmodium falciparum malaria vary between individuals and ethnic groups through poorly understood mechanisms. In addition to de novo synthesis of essential metabolites, P. falciparum engages in a series of scavenging, exchange and remodeling processes of host metabolites resulting in major metabolic perturbations during the blood-stage malaria. Knowledge of the metabolome changes in vivo in response to natural P. falciparum malaria in children and the effect of interethnic variations in these changes on the course of infection is very limited. In this study, we combine the power of prospective matched sampling, and integrative analysis of high resolution global in vivo metabolomic, lipidomic and joint host and parasite transcriptomic data to investigate the impact of infection on children of the Gouin, Mossi and Fulani ethnic groups in Burkina Faso. The main goal of this study is to investigate how serum metabolites and lipids could modulate host immune response to malaria and parasite proliferation. Our results reveal signature perturbations in nucleotide, amino acid, and lipid metabolism pathways in association with P. falciparum malaria and parasitemia. We identified perturbations in steroid biosynthesis as hallmark of P. falciparum infection. Integrative multi-omic analysis and immune cell proliferation assays revealed steroid-driven immunosuppression of T-lymphocytes function during infection with potential subsequent effect on parasite proliferation. Analysis of the less malaria-susceptible Fulani ethnic group demonstrates opposing steroid responses during infection supporting the immunosuppressive role of endogenous steroids during blood stage P. falciparum malaria. We provide an in vivo blueprint of remodeling and biosynthesis processes of phospholipids, the main building block for the cell membranes of the intraerythrocytic P. falciparum parasite. We also characterized in high resolution the changes in the levels of acyl chain saturation of phospholipid and triacylglycerol (TAG) molecules in the serum during infection. We provide insight on the implications of these changes on the parasite growth, hemozoin formation, and the importance of these changes for the survival of parasite. Interethnic comparisons revealed an impact for the Fulani lifestyle and dietary preference on their serum lipidome with insight for its potential modulatory role on the parasite development. We identified significant enrichment of milkfat-derived pentadecanoic acid (C15:0)- containing lysophospholipid molecule LPC (15:0) in Fulani children before and during infection, which could have a potential role in blocking sexual commitment of P. falciparum parasite during blood stage These results implicate the metabolome and lipidome in the mechanisms underlying immune response modulation, and parasite fitness and development during blood stage malaria, respectively. Our study also provides evidence on how environmental factors could influence the metabolome and subsequently disease phenotype. Finally, these findings advance our understanding of P. falciparum pathogenesis in vivo and identify potential new targets for better antimalarial therapeutic interventions.

Keywords: Multi-Omics, Host-Parasite, Interactions, Plasmodium, Falciparum Malaria