Whole Plasmodium exportome: Identification of survival and virulence factors

Despite recent encouraging results, malaria remains one of the main health problems globally. Most of malaria associated mortality and morbidity in humans is caused by Plasmodium falciparum the deadliest species know to infect humans. In addition P. vivax poses a considerable public health burden in S.E. Asia and is the most difficult to cure. To date, progress in our understanding of parasite biology and pathogenicity is slow, and there is an urgent need to expand the number of new molecular targets for intervention if elimination of human malaria is to be achieved. After invasion, parasites extensively modify and remodel the red-blood-cell to ensure their survival and promote virulence. Underlying these modifications are parasite proteins exported into the red-blood-cell cytoplasma. To date, the nature of these molecules remains elusive and could prove its downfall, providing new avenues for anti-disease/parasite intervention. The goal of this proposal is to determine the repertoire of exported proteins conserved across Plasmodium genus that are essential for parasite survival/virulence. We have recently identified an export signal named PLASMED in P. yoelii and used it to predict an expanded exportome; we now aim to extend our studies to P. falciparum and P. vivax. For this, The PLASMED exportome of both species will be predicted and refined using machine learning method. Conversely to in silico prediction, proteomic analysis will be used to identify the plasmodial proteins localised in the host cell-cytoplasma. Merging these exportomes will define a repertoire of conserved exported proteins which will be validated and functionally characterized using gene knockout and tagging. Phenotypes of genetically modified parasites will be assessed for biological as well as biomechanical changes. The data obtained here will not only address fundamental questions regarding host-cell remodelling, but will also provide new therapeutic targets able to block the parasite development/virulence.