Fusion mediators of the malaria parasite’s digestive vacuole and their role in the delivery of host cell hemoglobin

• Applicant: Dr. Joachim Michael Matz
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 540803070

Malaria is caused by unicellular parasites which repeat¬edly invade and lyse erythrocytes in the human bloodstream. Throughout its intraerythrocytic development, the most virulent malaria parasite, Plasmodium falciparum, consumes up to 80% of host cell hemoglobin by endocytosis. This occurs at the so-called cytostomes, prominent invaginations of the parasite surface. Vesicles filled with host cell cytosol traffic from the cytostomes to the parasite’s digestive vacuole, an acidified lysosome-like compartment where hemoglobin is proteolytically degraded. Internalization and catabolism of host cell hemoglobin are essential for parasite survival in the blood and constitute important adjusting screws for antimalarial drug susceptibility. However, the molecular mechanisms underlying membrane fusion between the transport compartments and the vacuole remain elusive. In a pilot study, we have identified two putative fusion mediators, called SNARE4 and SNARE9, which appear to be involved in hemoglobin delivery to the digestive vacuole. Both proteins localize to small vesicular organelles and the vacuolar membrane. Their genetic inactivation causes developmental arrest and is accompanied by intraparasitic accumulation of vesicular compartments that appear to be filled with host cell cytosol. Based on our observations, we hypothesize that SNARE4 and SNARE9 participate in a shared SNARE complex to cooperatively mediate fusion between the hemoglobin transport compartments and the digestive vacuole. To characterize the molecular functions of SNARE4/9, we will pursue five research aims: (1) to establish the origin of accumulating vesicles in SNARE4/9-deficient parasites, (2) to characterize the subcellular dynamics of SNARE4/9 in space and time, (3) to define SNARE4/9 membrane topology, (4) to determine whether both proteins participate in the same SNARE complex, and (5) to characterize the hemoglobin transport compartment by leveraging induced fusion defects. To achieve these goals, we will employ an integrated approach of advanced experimental genetics, versatile quantitative imaging and protein interaction analyses. Combined, the proposed investigations will shed light on the molecular workings of a central metabolic Achilles heel of the parasite – its critical dependency on host-derived macromolecules.

• DFG Programme: Research Grants