Formation and function of the parasitophorous vacuole membrane in Plasmodium falciparum-infected erythrocytes

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Malaria parasites cause disease by infecting red blood cells. During the process of invading these cells, the parasites become surrounded by a membrane, referred to as the parasitophorous vacuole membrane (PVM). Throughout the entire replication cycle inside the red blood cell, this membrane separates the parasite from the cytosol of the red blood cell, which consists primarily of haemoglobin. However, the membrane also makes the uptake of nutrients and the transport of proteins from the parasite to the red blood cell much more difficult. It is not understood why the parasite would maintain such a barrier, whereas related organisms that can also replicate in red blood cells can remove it and live free in the cytosol of the red blood cell. It is likely that the PVM performs an essential function, or multiple functions, for the parasites, but that function is entirely unclear. Also, it is not known how the PVM is made, maintained and expanded as the parasite grows inside the red blood cell. The aim of this research programme is to determine how the PVM is made and determine the role of the proteins that normally reside in the PVM in its development and maintenance, and ultimately answer the question how this membrane helps the parasite survive inside the red blood cell. Previous research has identified a protein, named PFA0210c, which may be involved in the formation of the PVM soon after the parasite has entered the red blood cell and again at later stages of the growth inside red blood cell. PFA0210c is a phospholipid transfer protein that can transfer phospholipids, the building blocks of cellular membranes, from one membrane to another. The PVM of parasites that do not produce this protein are much smaller than normal, indicating that potentially the role of PFA0210c is to transport phospholipids from the parasite to the PVM. Part of this research is aimed at discovering exactly how this protein functions and what its role in the formation of the PVM is. Another aspect of this study is the investigation of proteins that are known to reside in the PVM. Only about fifteen of such proteins are known, and twelve of them will be investigated: eleven members of a family of proteins called ETRAMPS and a protein called EXP1. By investigating these proteins, initially through the creation of parasites in which the genes that encode these proteins can be rapidly deleted through the addition of a small molecule, it may be possible to determine the function of these proteins. This will provide insight into the function of the PVM and hence the ability of the parasite to survive inside the red blood cell. Lastly, part of the research is aimed at the PVM itself. Parasites will be produced in which the synthesis of proteins that can break down phospholipids or produce large holes in membranes can be turned on. If this results in the loss of the PVM, then the role of the PVM can be observed directly by determining what happens to the parasite when it no longer has the protective coat that the PVM offers.Ultimately the study of these proteins and the PVM could be used to search for more anti-malarial compounds. PFA0210c has been shown to be essential for the survival of the parasite and several PVM proteins, including EXP1, could be essential proteins and do not resemble proteins in the human host - important characteristics for proteins that are the targets of anti-malaria drugs. Hence, not only could this research lead to much deeper insight into the interaction of the parasite with its host, it could stimulate the search for anti-malaria drugs that target these proteins.