Molecular basis of effector protein export in the malaria parasite Plasmodium falciparum

Malaria is a devastating parasitic disease that affects more than 200 million people annually, resulting in nearly 500,000 deaths each year. As of 2018, the World Health Organization estimates that 3.8 billion people, roughly half the world’s population, are at risk of contracting malaria, and the rise of drug-resistant parasites has created a desperate need for new anti-malarial drugs. While most intracellular pathogens export a limited repertoire of effector proteins to co-opt existing host-cell metabolic machineries, the malaria-causing parasite Plasmodium falciparum exports more than 10% of its proteome into its host, the human red blood cell, during the blood stages of its life cycle. The hundreds of proteins in the P. falciparum exportome extensively remodel host erythrocytes, creating the infrastructure needed to import nutrients, export waste, and evade the host immune system. The export of these hundreds of proteins is complicated by the fact that the malaria parasite conceals itself inside a parasitophorous vacuole (PV) derived from invagination of the host cell plasma membrane during invasion. Following secretion into the PV, proteins destined for export must be unfolded and transported across the PV membrane (PVM) into the host cell in an ATP-dependent process. The export pathway is essential for parasite survival, making members of the pathway attractive potential drug targets. The complexity and breadth of its host-cell remodeling machinery make P. falciparum a rich and exciting system for the study of host-pathogen interactions. However, many of the molecular mechanisms underlying this parasite’s ability to hijack human red blood cells remain enigmatic, as much of the P. falciparum proteome has proven recalcitrant to structural and biochemical characterization using traditional recombinant approaches. The proposed work will provide insight into the pathogenesis of this deadly disease, identify new malarial drug targets, and enable structure-guided design of novel anti-malarial therapeutics.

Project details

Basic Science

Sep 2020 — Aug 2025

$1.22M

United States