Investigating Plasmodium reticulocyte invasion as a route to elevating the spread of malaria

The most severe form of human malaria and the majority of malaria-related cardiac dysfunction is caused by Plasmodium falciparum. The malaria parasite has a complex life-cycle split between a human host and a mosquito. The symptoms of malaria are the result of the blood stage infection, where parasites repeatedly invade, replicate asexually and destroy the host’s red blood cells (RBCs). In parallel to this cycle, a small number of parasites become committed to forming sexual cells called gametocytes that are taken up by mosquitos to enable transmission to a new host. Invasion of all forms of blood-stage P. falciparum into RBCs requires direct interactions between ligands on the parasite’s surface and receptors on the host cell surface. The parasite ligands can vary in expression and sequence, and distinct combinations dictate the host receptors the parasite uses to gain entry into the RBC. The RBCs within the bloodstream vary in age, with young RBCs (reticulocytes) being more metabolically active and having a greater abundance and variety of proteins on their surface compared to older RBCs (normocytes). P. falciparum can invade both normocytes and reticulocytes, however demonstrating a preference for the latter. Reticulocytes make up ~1-2% of circulating RBCs. The selective invasion into this minor RBC population is associated with reduced antimalarial drug potency in Plasmodium spp and, in parallel, enhanced gametocyte formation, the combination of which is conducive to the spread of drug resistance. Currently, the ligand-receptor interactions involved in the preference of P. falciparum parasites for invading reticulocytes are unknown. This might have tangible outcomes in informing vaccine development focused on blocking transmission.

Enabling Technologies & Assays

Jan 2019 — Dec 2020

$104,000

United States