Microbiology & Immunology - Theses
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ItemPhosphorylation of apical membrane antigen 1:a key event in erythrocyte invasion by Plasmodium falciparum( 2016)The phylum Apicomplexa comprises a large group of human and animal parasites with wide medical and socioeconomic significance, including the most virulent causative agent of malaria (Plasmodium falciparum). These are obligate intracellular parasites that actively and rapidly invade host cells via complex and coordinated receptor-ligand interactions and signal transduction events. Invasion of erythrocytes allows P. falciparum to establish a “blood-stage” infection, where all of the clinical manifestations of disease arise. Apical Membrane Antigen 1 (AMA1) is a specialised membrane-spanning invasion ligand that serves to engage the host cell by establishing membrane junction at the host-parasite interface to maintain close cell-cell contact during invasion. The cytoplasmic domain of AMA1 appears to be extensively phosphorylated before erythrocyte invasion, but whether phosphorylation plays a role in regulating the ligand’s function remains unclear. We have uncovered a highly organised signal cascade that leads to hierarchical phosphorylation of serine 610 and threonine 613 for functional efficiency of AMA1 during erythrocyte invasion. Cyclic AMP-dependent protein kinase A (PKA) was shown to phosphorylate S610, which acts as a priming step for subsequent phosphorylation of T613 by glycogen synthase kinase 3. Adenylyl cyclase β (ACβ) and phosphodiesterase β (PDEβ) were shown to stimulate and inhibit activity of PKA respectively, thereby regulating phosphorylation of both S610 and T613. This is the first indication that phosphorylation is used by P. falciparum to modulate the activity of invasion ligands. We have implicated a number of key enzymes in this signal cascade that could be systematically targeted for drug design to disrupt AMA1 phosphorylation and invasion, and terminate infection. This work has contributed to a greater understanding of the means by which malaria parasites establish infection and could open many avenues for the development of novel therapeutics against malaria.