The apicoplast is important for the viability and persistence ofToxoplasma gondiibradyzoites

Abstract

Toxoplasma gondii is responsible for toxoplasmosis, a disease that can be serious when contracted during pregnancy, but can also be a threat for immunocompromised individuals. Acute infection is associated with the tachyzoite form that spreads rapidly within the host. However, under stress conditions, some parasites can differentiate into cyst-forming bradyzoites, residing mainly in the central nervous system, retina and muscle. Because this latent form of the parasite is resistant to all currently available treatments, and is central to persistence and transmission of the parasite, new specific therapeutic strategies targeting this developmental stage need to be discovered. T. gondii contains a plastid of endosymbiotic origin called the apicoplast, which is an appealing drug target because it is essential for tachyzoite viability and contains several key metabolic pathways that are largely absent from the mammalian host. Its function in bradyzoites, however, is unknown. Our objective was thus to study the contribution of the apicoplast to the viability and persistence of bradyzoites during chronic toxoplasmosis. We have used complementary strategies based on stage-specific promoters to generate conditional bradyzoite mutants of essential apicoplast genes. Our results show that specifically targeting the apicoplast in both in vitro or in vivo-differentiated bradyzoites, leads to a decrease in cyst burden or a loss of bradyzoite viability, highlighting the importance of this organelle for this developmental stage. This validates the apicoplast as a potential area to look for new therapeutic targets in bradyzoites, with the aim to interfere with this currently incurable parasite stage.

TgATG9 is required for autophagosome biogenesis and maintenance of chronic infection inToxoplasma gondii

“…Our TgATG9 conditional knockdown mutant can be used in future metabolomic or proteomic studies for this purpose. While several other pathways have been reported to be critical to bradyzoite survival including storage and utilization of amylopectin granules, maintaining structural integrity of the cyst wall, and apicoplast-related functions, our results underscore the importance of autophagy in this stage of T. gondii [8,[63][64][65][66].…”

In vivoCRISPR screens identify novel virulence genes among proteins of unassigned subcellular localization inToxoplasma

“…Considering that the apicoplast evolved from secondary endosymbiosis (41) and that the zinc finger domain in TgRimM is essential for its function in our study, ApiRimM might facilitate rRNA maturation and proteostasis in the apicoplast. Previous studies on Toxoplasma apicoplast have shown that apicoplast function is essential for the parasite in vitro survival and growth (42–44). Moreover, apicoplast-assigned proteins in hyperLOPIT showed a small number of in vitro dispensable proteins (7), also supporting its bare essentiality.…”

Progressive heterogeneity of enlarged and irregularly shaped apicoplasts inP. falciparumpersister blood stages after drug treatment

“…A more recent investigation of Toxoplasma bradyzoites, the persister forms of T. gondii responsible for chronic infections, indicated that the apicoplast is vital for long-term survival of bradyzoites. Interestingly, tissue cysts derived from mutant parasites with a non-functional dynamin-related protein (Drp) display enlarged, reticulated apicoplasts and compromised persistence (51).…”