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Role of Lipid Rafts and Phosphoinosiitides in Entamoeba Histolytic Virulence

Objective

Entamoeba histolytica is the causative agent of amoebic dysentery and liver abscess. It ranks third as a worldwide cause of morbidity and has been classified as a Category B bioterrorism agent. Therefore, there is elevated priority to understand the biology of and develop innovative detection and therapeutic strategies. E. histolytica trophozoites will encounter a variety of host cells and macromolecules during infection. <P>It is postulated that these extracellular components trigger signaling in the parasite that lead to changes in virulence. With the rate at which the components of signaling pathways are being discovered in E. histolytica, the new challenge is to understand the temporal and spatial regulation of signaling events in these cells.<P> In other eukaryotes, lipid rafts (cholesterol- and sphingolipid-rich plasma membrane domains), along with the actin cytoskeleton, and phosphoinositides (PIs), compartmentalize signaling events in the plasma membrane. Recently, E. histolytica cells were shown to possess raft-like plasma membrane domains. The colocalization of rafts with an important signaling/adhesion molecule, the galactose/N-acetylgalactosamine (Gal/GalNAc) lectin, suggests that rafts may also participate in signaling in E. histolytica.<P> In the proposed studies, the biological role of E. histolytica lipid rafts, as well as of several PIs, will be explored.

More information

Non-Technical Summary: Entamoeba histolytica, a protozoan parasite, is the causative agent of amoebic dysentery (amoebic colitis), invasive amoebiasis, and liver abscess in developing countries that cannot prevent its fecal-oral spread. Infection is acquired by ingestion of the cyst form of the parasite in contaminated food and water. Since this protozoan can infect large numbers of people through contaminated water and/or food, is difficult to diagnose, and can be genetically manipulated, the NIH has classified E. histolytica as a Category B bioterrorism agent. Therefore, there is elevated priority to understand the cellular processes of this pathogen. This, in turn, may lead to the development of innovative detection, prevention and therapeutic strategies. In the proposed studies, the biological role of E. histolytica lipid rafts, small membrane domains, will be explored. In particular, the role of lipid rafts in parasite vesicle trafficking, intracellular signaling, and actin cytoskeletal rearrangements will be analyzed. Since these cellular functions likely regulate virulence, these studies will contribute significantly to understanding the infectious process of this food- and water-borne pathogen. <P> Approach: In the first Aim, the mechanisms regulating raft function will be examined. In particular the nature of the raft compartment, the mechanism by which the Gal/GalNAc lectin interacts with these membranes, and additional virulence-associated raft roles will be addressed. In the second Aim, the connection between lipid rafts, vesicle trafficking and actin will be assessed utilizing biochemical approaches as well as genetic approaches using mutants in which these cellular components are uncoupled. Finally, in the third Aim, the role of PIs in parasite virulence functions will be examined. Since vesicle trafficking, actin cytoskeletal rearrangements and signaling likely regulate virulence, these studies will contribute significantly to understanding the pathogenicity of E. histolytica.

Investigators
Temesvari, Lesly
Institution
Clemson University
Start date
2006
End date
2012
Project number
SC-1700312
Accession number
207117