Malaria is transmitted to humans by the injection of Plasmodium sporozoites into the skin during the bite of an infectious female Anopheles mosquito. Sporozoites leave the circulation by traversing the sinusoidal cell layer and infect hepatocytes and form liver stages (LS). LS parasites reside in a membrane-bound compartment termed the parasitophorous vacuole membrane (PVM), where they differentiate into exoerythrocytic merozoites. Once development within the liver is complete, parasites exit the hepatocyte as packages of merozoites that bud off from the cell (called merosomes) and re-enter the circulation and invade red blood cells leading to clinical symptoms of malaria. We focus on Plasmodium LS infection as this stage is brief, critical and asymptomatic: success would eliminate all initial and relapsing disease and subsequent transmission.
Key to an intracellular lifestyle of any pathogen is the ability to manipulate and divert host nutrients while evading recognition by the immune system. Plasmodium liver-stage (LS) parasites replicate within the parasitophorous vacuole (PV), formed during invasion. The main interface between the parasite and hepatocyte is the parasitophorous vacuole membrane (PVM) that surrounds the PV. The PVM gets modified by the parasite as it develops and matures over the subsequent period, presumably to support the acquisition of host nutrients needed for parasite growth. The range of transport activities at this interface is largely unknown. The LS parasite relies on a precise intracellular environment that supports its growth. Specific mechanisms by which the LS Plasmodium sequesters the host nutrients for their survival is not known. Understanding the nutrient trafficking mechanism at the host-parasite interface would significantly serve as to better understand the molecular factors driving the triggers of active and dormant LS forms.
Central focus of our lab is to understand 1) host-parasite interactions at the cell surface that facilitates parasite entry, 2) mechanism by which the intracellular liver-stage parasite acquires nutrients from the host cells, and how they traffic these nutrients across PVM and the parasite membrane.