Doctoral thesis
Open access

Toxoplasma gondii exit from host cells: Contributions of organelle biogenesis, vesicular fusion and signaling towards microneme exocytosis

Imprimatur date2020
Defense date2020

The Apicomplexa phylum includes a large group of obligate intracellular protozoan parasites responsible for important diseases in humans and animals. Toxoplasma gondii is a widespread parasite with considerable versatility, capable of infecting virtually any cell types in all warmblooded animals, including humans. This outstanding success can be attributed at least in part to an efficient and continuous sensing of the environment, with a ready-to-adapt strategy and the unique capabilities of T. gondii to bypass its definitive host for transmission. During this thesis, we have focused in egress, which is temporally orchestrated and underpinned by the exocytosis of secretory organelles called micronemes. We have identified a subset of SNARE proteins involved in endosome sorting and targeting, including some associated to micronemal proteins dispatch/traffic from the ER and through the endosomal-like compartment to the micronemes. We have also highlighted the importance of plasma membrane phosphatidylserine as an important phospholipid to trigger microneme exocytosis. The effect of phosphatidylserine at the plasma membrane is at least partially mediated by the binding of the double C2 domain containing protein DOC2.1, which is essential for microneme exocytosis. The level of phosphatidylserine at the inner leaflet of the plasma membrane is controlled by a P4-ATPase (flippase), which is as well essential for microneme secretion. In parallel, we have dissected the first steps in the signalling cascade leading to parasite exit form host cells. We show that diacylglycerol kinase 2 is secreted into the parasitophorous vacuole, where it produces phosphatidic acid. Phosphatidic acid acts as an intrinsic signal that elicits egress in absence of extrinsic signals upstream of an atypical guanylate cyclase (GC), composed of a P4-ATPase and two GC catalytic domains. Assembly of GC at the plasma membrane depends on two associated cofactors — the cell division control 50.1 (CDC50.1) and a unique GC organizer (UGO). This study reveals the existence of a signalling platform that responds to an intrinsic lipid mediator and extrinsic signals to control programmed and induced egress. Moreover, the GC-UGO components of the platform are critical to integrate the signals implicated in host cell invasion.

Citation (ISO format)
BISIO SABARIS, Hugo. Toxoplasma gondii exit from host cells: Contributions of organelle biogenesis, vesicular fusion and signaling towards microneme exocytosis. 2020. doi: 10.13097/archive-ouverte/unige:169516
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