Essential function of a putative glycosyltransferase in P. falciparum

The lethal form of human malaria is caused by the intracellular parasite Plasmodium falciparum, which causes nearly 450,000 deaths every year. Infection by these parasites results in ~250 million infections each year. However, there are no effective vaccines against malaria and the parasite has gained resistance to all antimalarial drugs used in the clinic. Further, these drug-resistant strains are spreading throughout the world. Therefore, it is crucial to identify essential druggable pathways used by the parasite to grow within human host cells. One such poorly understood but essential pathway is the modification of parasite proteins by sugar molecules or glycans. In other model organisms, this process is essential for protein function and mostly occurs in the secretory pathway. Recent work in Plasmodium parasites has shown that glycan modification of several parasite surface ligands play an essential role in parasite transmission and its development within the mosquito vector. But little is known about the function, if any, of glycosylation during the clinically important intraerythrocytic growth of P. falciparum. We recently identified a putative glycosyltransferase as an essential interactor of a heat shock protein residing in the endoplasmic reticulum. To study its function during the intraerythrocytic stages of parasite growth, we generated conditional mutants for this protein.

 Our preliminary data show that this protein is essential for parasite growth within human red blood cells and is required for the egress of daughter parasites from the host cell at the end of the intraerythrocytic life cycle. Using cellular, biochemical, and genetic approaches, we will define the function of this gene during egress of daughter parasites. The essentiality of the putative glycosyltransferase activity for parasite survival will be tested. The proposed studies will use recombinant enzyme to define the enzymatic activity of this glycosyltransferase. Proximity-dependent biotinylation approaches combined with mass spectrometry will be used to identify interactors as well as putative substrates. The success of this project will reveal novel and essential glycosylation pathways used by the parasite for asexual expansion in human red blood cells.

NIH project details

Enabling Technologies & Assays

Apr 2021 — Mar 2023

$415,250

United States