Red Cell Membrane Skeleton and Malaria Infection

New York Blood Center, New York NY

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Abstract

Description (provided by applicant) Our objective is to continue to examine the structural changes occurring in the malaria-infected red cell and to elucidate the functional consequences of interaction between red cell membrane proteins and proteins elaborated by intraerythrocytic stages of the malarial parasite. Our hypothesis is that the parasite-mediated changes in red cell properties are the result of different parasite-derived proteins interacting with specific red cell membrane proteins. To accomplish this, we propose the following specific aims: 1) Define the specific interacting domains of P. falciparum proteins, specifically PfEMP3, FEST, Pf332 and PFB085c with red cell membrane proteins. These studies will provide important clues into functional consequences of the defined interactions between red cell and P. falciparum proteins. 2) Define how the ability of red cell proteins to interact with their normal binding partners is altered as a consequence of their interaction with specific malaria proteins. This will give us a detailed understanding of how normal protein-protein interactions in the red cell are altered by malaria infection and the effect of these altered interactions on cellular properties. 3) Derive the crystal structure of the MESA-4.1R complex to give us structural insight into the interaction between a malaria protein and its cognate host protein. 4) Determine the in vivo consequences of the interactions between malaria proteins and host proteins, in particular the MESA-4.1R interaction, in a murine malaria model. In vivo study of infection using 4.1-deficient mice will help determine the mechanism for failure of parasite growth in these cells and may suggest novel therapies aimed at interruption of parasite replication. 5) To examine the involvement of host structures to the process of invasion, we will observe by videomicroscopy the invasion of normal and mutant red cells by single merozoites, following the movement of membrane skeleton components during this process with highly sensitive fluorescence microscopy. This information will enhance our understanding of a still poorly understood process. Furthermore, it will allow us to formulate a model at the molecular level as to how invasion proceeds and suggest ways in which it might be interfered with. Understanding how the parasite causes these changes in red cell membrane functions should give us new insights into the biology of an important human pathogen and into the normal functioning of the red cell membrane skeleton.