School of Biomedical Sciences - Theses
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ItemCharacterization of cyclic nucleotide-mediated signal transduction pathways in Toxoplasma gondii( 2017)T. gondii is amongst the most common human pathogens, chronically infecting more than 30% of the human population. T. gondii has a complex life cycle, often spanning multiple hosts. T. gondii parasites invade target host cells to establish infection. Residing inside host cells, parasites are immotile and active replicate. After multiple rounds of replication, T. gondii activates their motility and egress from host cells. Invasion and egress relies on parasites motility, which is strictly controlled by a number of second messenger-mediated signalling transduction pathways. The signalling pathways that controls parasite motility have become a focus of investigations in the past two decades due to its potential as a therapeutic target. Previous studies showed that activation of Ca2+-mediated signalling pathways and cGMP-mediated signalling pathways drives parasites microneme secretion and motility. Conversely, cAMP-mediated signalling pathways may work as suppressors on parasites motility. In Chapter 3, I evaluated the function of a putative guanylyl cyclase in T. gondii asexual growth. TgGC accumulates at apical tip of the parasites and alters its localization during intracellular growth and extracellular motility. TgGC is critical for T. gondii growth and it plays an important role in parasites microneme secretion, invasion and egress, highly suggestive of its function in cGMP generation. We showed that cGMP-mediated signalling pathways localize upstream of cytosolic Ca2+ rise and could be occurring by activation of phosphatidylinositol-specific phospholipase C. In Chapter 4, I investigated the regulation of cAMP signalling. I identified the cAMP-dependent protein kinase A regulatory domain TgPKAr that regulates activity of catalytic domain TgPKAc1, which has been suggested as a negative regulator of motility and Ca2+ signalling. TgPKAr and TgPKAc1 localize at the parasite periphery, which occurs likely through palmitoylation and myristoylation on the N-terminal TgPKAr sequence. Overall, my work highlights the pivotal role signal transduction pathways play in T. gondii parasites and sheds light on the complex hierarchy and interplay between second messengers-mediated signalling cascades that regulate parasites motility and infectivity.