Lipid rafts in the human parasite 'Schistosoma mansoni'

The surface of schistosomes is covered by a syncytial cytoplasmic tegument, which has a unique architecture comprising two closely-opposed lipid bilayers, a plasma membrane and a membranocalyx. This structure represents the interface between the parasite and host and is therefore believed to have a role in complex host-parasite interactions. The observation that several proteins, including signalling proteins and receptors, can segregate into lipid rafts present in the plasma membrane, providing a concentrated platform for signal transduction, has sparked interest in the biological functions of lipid rafts. Here, the importance of these microdomains to schistosome biology and function in the context of host-parasite interactions is investigated. Using confocal laser scanning microscopy (CLSM), the temporal clustering of lipid rafts in response to human epidermal growth factor (EGF) stimulation was demonstrated in the tegument of Schistosoma mansoni during early somule development in vitro. Further, EGF receptors (EGFRs) and insulin receptors (IRs) were mapped on the surface of somules using FITC-labelled EGF and -insulin respectively, both of which were discovered towards the anterior cone of the parasite, consistent with the localisation of lipid rafts. Cholesterol depletion of lipid rafts using methyl-b-cyclodextrin (MbCD) abrogated the expression of/binding to EGFRs and IRs at the schistosome surface. Moreover, phosphorylation/activation of signalling pathways including protein kinase C (PKC), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK) and Akt were modulated significantly by cholesterol depletion. Finally, lipid raft disruption, and inhibition of EGFRs using canertinib, profoundly reduced somule motility and survival as well as reducing cell proliferation and somule growth/development. This study also provided the first known proteomic analysis of S. mansoni somule detergent resistant membranes (DRMs) with 41 proteins identified in the triton-insoluble (TI) fraction, of which many are target molecules for novel drug/vaccine discovery against schistosomiasis. Thus, lipid rafts are important for communication between the schistosome and human host and are also likely to be important for the initial development and survival of the parasite within the host. The rafts therefore represent a potential target for the design of innovative therapeutic approaches to combat this devastating disease.