Receptor signalling mediating malaria parasite motility
Date du début: 1 avr. 2012,
Date de fin: 31 mars 2017
Plasmodium sporozoites are the motile forms of the malaria parasite injected into the host by a mosquito. Sporozoite motility is essential for tissue penetration as well as host cell invasion and thus pathogenesis suggesting that blocking motility could potentially add a new way in controlling malaria. It is dependent on a parasite specific myosin, a highly divergent actin and plasma membrane proteins, adhesins that link the substrate to the actomyosin motor. We want to understand the molecular and biophysical basis that underlies the motility of sporozoites to eventually be able to block it. Consequently, we developed methods that allow a systematic probing of key variables important in motility in order to reveal the basic mechanisms of sporozoite locomotion and to screen for small molecules that inhibit motility. Using these assays, we made a number of groundbreaking observations on the cellular and molecular level that gave new insights into the mechanisms of sporozoite adhesion and motility. For example, the dynamic, actin-dependent turnover of adhesion sites was found to be a key factor in sporozoite motility. It is our ultimate goal to understand sporozoite motility to a degree that we can provide a comprehensive dynamic model of sporozoite movement. With the current proposal we aim at unravelling the initial molecular events leading to sporozoite motility focussing on three different adhesins that are known or suspected to be involved in motility. We hypothesize that outside-in signalling leading to actin rearrangements originates from the formation of homo- or heterodimers between these adhesins. Additionally we suggest that inside-out signalling contributes to modulation of adhesion strengths mediated by these adhesins. To test these hypotheses we will generate recombinant parasites that lack two adhesins or express fluorescently tagged adhesin fusions, chimeric or mutant adhesins and investigate these with our recently developed toolbox of novel assays.
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