Restriction Checkpoint Controls Bradyzoite Development in Toxoplasma gondii

Naumov, Anatoli; Wang, Chengqi; Chaput, Dale; Ting, Li-Min; Alvarez, Carmelo A.; Keller, Thomas E.; Ramadan, A. A.; White, Michael; Kim, Kami; Suvorova, Elena S.

doi:10.1128/spectrum.00702-22

Cited by 7 publications

(4 citation statements)

References 73 publications

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“…The severity of the clinical symptoms depends on the degree of tachyzoite replication, which means that an individual's immune system is crucial in defining the clinical manifestations. 23 Administration of spiramycin at 100 mg/kg BW orally for three days effectively inhibited tachyzoite replication, as proved by the significantly lower difference in the mean number of tachyzoites present in the peritoneal fluid between group II and group I (Table 4). Spiramycin is an antibiotic and an antiparasitic macrolide agent that is considered the drug of choice against T. gondii in pregnancy.…”

Section: Number Of Tachyzoitesmentioning

confidence: 87%

Moringa oleifera Leaf Ethanol Extract Inhibits Toxoplasma gondii Tachyzoites Replication

Wihanto

Waworuntu

Tedyanto

et al. 2023

IJTID

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The various infection routes of Toxoplasma gondii that are close to daily life strongly support the incidence of toxoplasmosis. The emergence of drug-resistant Toxoplasma gondii strains raises future concerns. Moringa leaf ethanol extract has been shown to have several anti-pathogen activities, which could have an anti-Toxoplasma effect. This research was conducted to analyze the anti-Toxoplasma effect of moringa leaf ethanol extract against tachyzoites replication in Toxoplasma gondii and the correlation between extract doses with the number of tachyzoites. Mice were divided into five groups. The negative control group (Group I) received CMC-Na solution. The positive control group (Group II) received spiramycin 100 mg/kg BW. The treatment groups received moringa leaf ethanol extract 250 mg/kg BW (group III), 500 mg/kg BW (group IV), and 1000 mg/kg BW (group V), respectively. Mice were injected with 1 x 105 tachyzoites/0.1 mL/mice intraperitoneally on the first day. Moringa leaf ethanol extract and spiramycin were given orally once daily for three days. The number of tachyzoites in the intraperitoneal fluid was calculated on the fifth day. The results have shown that there were significantly lower differences (P < 0.05) in group IV (P = 0.021) and group V (P = 0.022) compared to group I. There was also a significant negative correlation between the extract doses and the number of tachyzoites (P = 0.000; r = -0.781). Moringa oleifera leaf ethanol extract has an anti-Toxoplasma effect by inhibiting the tachyzoite replication at 500 mg/kg BW and 1000 mg/kg BW.

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Section: Number Of Tachyzoitesmentioning

confidence: 87%

Moringa oleifera Leaf Ethanol Extract Inhibits Toxoplasma gondii Tachyzoites Replication

Wihanto

Waworuntu

Tedyanto

et al. 2023

IJTID

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“…Moreover, the three major clonal lineages of T. gondii that have different growth characteristics, vary in their ability to form tissue cysts, reflecting an inverse association between tachyzoite replication and bradyzoite differentiation. Although RH tachyzoites have been reported to express bradyzoite-specific genes under stress conditions(17), type I strains typically exhibit rapid replication but are largely incapable of forming mature cysts in vitro or in vivo (54, 55). In contrast, type II/III strains proliferate relatively slowly and readily convert to bradyzoites under stress conditions (54, 55).…”

Section: Discussionmentioning

confidence: 99%

“…Although RH tachyzoites have been reported to express bradyzoite-specific genes under stress conditions(17), type I strains typically exhibit rapid replication but are largely incapable of forming mature cysts in vitro or in vivo (54, 55). In contrast, type II/III strains proliferate relatively slowly and readily convert to bradyzoites under stress conditions (54, 55). Tg68 tachyzoites replicate at a significantly slower rate and are more permissive for bradyzoite differentiation under alkaline stress in vitro in comparison with ME49 tachyzoites, supporting the correlation between slower replication and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Constitutive upregulation of transcription factors underlies permissive bradyzoite differentiation in a natural isolate ofToxoplasma gondii

Xia,

Fu,

Huang

et al. 2024

Preprint

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Toxoplasma gondii bradyzoites play a critical role in pathology due to their long-term persistence in intermediate hosts and their potential to reactivate, resulting in severe diseases in immunocompromised individuals. Currently there is no effective treatment for eliminating bradyzoites. Hence, better in vitro models of T. gondii cyst development would facilitate identification of therapeutic targets for bradyzoites. Herein we characterized a natural isolate of T. gondii, called Tg68, which showed slower in vitro replication of tachyzoites, and permissive bradyzoite development under stress conditions in vitro. Transcriptional analysis revealed constitutive expression in Tg68 tachyzoites of the key regulators of bradyzoite development including BFD1, BFD2, and several AP2 factors. Consistent with this finding, Tg68 tachyzoites expressed high levels of bradyzoite-specific genes including BAG1, ENO1, and LDH2. Moreover, after stress induced differentiation, Tg68 bradyzoites exhibited gene expression profiles of mature bradyzoites, even at early time points. These data suggest that Tg68 tachyzoites exist in a pre-bradyzoite stage primed to readily develop into mature bradyzoites under stress conditions in vitro. Tg68 presents a novel model for differentiation in vitro that will serve as a useful tool for investigation of bradyzoite biology and development of therapeutics.

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“…Mass-spectrometry. Protein samples were prepared for mass spectrometry-based proteomic analysis using s-traps (Protifi) as previously described [76,77]. Proteins were reduced with 20 μM dithiothreitol (DTT) for 10 minutes at 95°C, followed by a 30-min alkylation with 40 μM Iodoacetamide (IAA).…”

Section: Proteomic Analysismentioning

confidence: 99%

Essential role of the Conserved Oligomeric Golgi complex inToxoplasma gondii

Marsilia,

Batra,

Pokrovskaya

et al. 2023

Preprint

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Survival of the apicomplexan parasite Toxoplasma gondii depends on the proper functioning of many glycosylated proteins. Glycosylation is performed in the major membranous organelles ER and Golgi apparatus that constitute a significant portion of the intracellular secretory system. The secretory pathway is bidirectional: cargo is delivered to target organelles in the anterograde direction, while the retrograde flow maintains the membrane balance and proper localization of glycosylation machinery. Despite the vital role of the Golgi in parasite infectivity, little is known about its biogenesis in apicomplexan parasites. In this study we examined T. gondii Conserved Oligomeric Golgi (COG) complex and determined that, contrary to predictions, T. gondii expresses the entire eight-subunit complex and each complex subunit is essential for tachyzoite growth. Deprivation of the COG complex induces a pronounced effect on Golgi and ER membranes, which suggests the T. gondii COG complex has wider role in intracellular membrane trafficking. We demonstrated that besides its conservative role in protein glycosylation and retrograde intra-Golgi trafficking, the COG complex also interacted with anterograde and novel transport machinery. Furthermore, we identified coccidian-specific components of the Golgi transport system: TgUlp1 and TgGlp1. Protein structure and phylogenetic analyses revealed that TgUlp1 is an adaptation of the conservative Golgi tethering factor Uso1/p115, and together with Golgi-localized TgGlp1, TgUlp1 showed dominant interactions with the trafficking machinery that predicted to operate the endosome-to-Golgi recycling. Together, our study showed that T. gondii had expanded the function of the conservative Golgi tethering COG complex and evolved additional regulators of the transport likely to serve parasite-specific secretory organelles.

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Restriction Checkpoint Controls Bradyzoite Development in Toxoplasma gondii

Abstract: Toxoplasma gondii is a virulent and abundant human pathogen that puts millions of silently infected people at risk of reactivation of the chronic disease. Encysted bradyzoites formed during the chronic stage are resistant to current therapies.

Cited by 7 publications

References 73 publications

Moringa oleifera Leaf Ethanol Extract Inhibits Toxoplasma gondii Tachyzoites Replication

Moringa oleifera Leaf Ethanol Extract Inhibits Toxoplasma gondii Tachyzoites Replication

Constitutive upregulation of transcription factors underlies permissive bradyzoite differentiation in a natural isolate ofToxoplasma gondii

Essential role of the Conserved Oligomeric Golgi complex inToxoplasma gondii

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