protein secretion pathways of malaria-causing parasites
Research in the Muralidharan lab is aimed at understanding the biology of Plasmodium, the deadly human parasite that causes malaria. It is a disease that afflicts nearly 250 million people and causes almost a half a million deaths each year. Our goal is to uncover the molecular mechanisms that drive the parasitic life cycle of Plasmodium. The aim of this research is to leverage our knowledge of parasite biology towards development of intervention strategies that disrupt the disease process. We deploy a wide variety of tools to study the parasite including CRISPR/Cas9 genome engineering, cellular biology, chemical biology, molecular biology and biochemistry.
Our research focuses on organelle biology in this deeply branched eukaryote. We are particularly interested in the organization and function of the secretory pathway in two parasite specific biological processes: 1. The export of parasite effectors to the host red blood cell. 2. Egress of the parasite daughter cells from the infected red blood cell.
Export of parasite effector proteins to the host red blood cell
The clinical manifestations of malaria, including death, are caused by the growth of P. falciparum within the host red blood cell (RBC). To build a suitable habitat for growth inside RBCs, the malaria parasite completely transforms the host cell. It changes the metabolism of the RBC, makes the RBC more rigid such that it is harder for the infected RBC to pass through capillaries, modifies the RBC membrane to allow for favorable movement of nutrients, and alters the binding properties of the RBC so that the infected cell can bind to the endothelial cells lining blood vessels. The sum of these changes leads to disease and death, for instance, binding of the P. falciparum infected RBC to endothelial cells can clog blood vessels in the brain leading to clots that eventually result in death. The subjugation of the infected RBC is accomplished through the action of several hundred proteins that the parasite transports to the host cell via poorly understood mechanisms. The export of parasite effector proteins is essential for transforming the RBC and therefore, for causing disease. Parasite effector proteins that are synthesized in the parasite cytoplasm need to be transported across three or four cellular membranes in order to reach their site of action in the host RBC. We are interested in identifying the molecular mechanisms that recognize, sort, and transport these parasite effectors to the infected RBC.
Egress of plasmodium from their host red blood cells
Parasite proliferation requires invasion and growth within the infected red blood cell (RBC). The final step in this process is egress of the daughter parasites from the host RBC. At the end of schizogony, the daughter merozoites have to rupture out of two membranes, the parasitophorous vacuole (PV) membrane and the RBC membrane. The parasite prepares for this pivotal event during the final stages of the asexual cycle by generating several new organelles such as micronemes, exonemes, and rhoptries. The parasite ER is thought to play a central role in this process but no proteins in the ER have been shown to play role in this biological process. Therefore, we are interested in understanding how the parasite ER regulates egress and the function of ER proteins in this critical part of the Plasmodium life cycle.