Understanding host-parasite interactions during Plasmodium red blood cell invasion

Malaria continues to burden human health on a global scale and, with the majority of the over 600,000 annual deaths being children below the age of five, the disease is particularly cruel. The causative agents of malaria, parasites of the Plasmodium genus, start the symptomatic blood stage of infection by invading and replicating within erythrocytes. Invasion depends on multiple interactions between the protozoan intruder and its future host cell, and parasites of different species evolved different strategies and molecular machineries for invasion. Intriguingly, it is becoming increasingly clear that the interplay between parasite and host reaches beyond receptor-ligand interactions at the red cell surface. Today, knowledge on these processes remains scarce, which is at least in part explained by the difficulties linked to the genetic modification of the enucleated red blood cell (RBC). To make RBCs more accessible to functional studies, we invested into the work with immortalised RBC precursors that can be genetically engineered and subsequently differentiated into red cells supporting Plasmodium invasion and development. In addition to conventional knockout approaches, genetic tools were established that allow heterologous gene expression, endogenous tagging and the conditional knockdown of proteins in these cells. A high content imaging-based assay was further developed that allows quantifying invasion of Plasmodium parasites into genetically modified host cells. Combined with the capacity to produce these RBCs at high quantities, it is believed that this system paves the way for studying host-parasite interactions at a hitherto impossible level. The latter serves as a model for the most widespread human malaria parasite P. vivax that is refractory to in vitro cultivation. First, we aim at uncovering the mechanistic role of the essential invasion ligand CyRPA and its interplay with erythrocyte receptor complexes. Of note, P. falciparum and P. vivax/knowlesi interact with different host determinants, implying different, yet elusive functions of the highly conserved CyRPA during invasion. Second, this project will functionally characterise the signalling pathways elicited within erythrocytes upon making contact with invasion forms of both parasite species and investigate the consequences and role of these events on cytoskeletal rearrangements of the host cell. By placing emphasis on inter-species differences, we are convinced that this project will contribute substantially to understanding Plasmodium invasion – a prime malaria vaccine target. In addition, we believe that the proposed work will provide functional insight on the targetability of host factors during malaria infections.

Project details

Basic Science

Jan 2025 — Dec 2028

$674,931

Switzerland