Treatment of Toxoplasmosis: Historical Perspective, Animal Models, and Current Clinical Practice

Dunay, Ildikò Rita; Gajurel, Kiran; Dhakal, Reshika; Liesenfeld, Oliver; Montoya, José G.

doi:10.1128/cmr.00057-17

Cited by 323 publications

(253 citation statements)

References 260 publications

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“…The search for new anti-Toxoplasma gondii drugs has been active for several decades [12,13], but only a few drugs are currently approved for use in humans [1,27]. Although sulfa drugs can be effectively used for the prevention and control of T. gondii infection in humans and animals, their side effects should not be ignored [28].…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional changes in Toxoplasma gondii in response to treatment with monensin

Zhai

Elsheikha

et al. 2020

Parasites Vectors

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Background: Infection with the apicomplexan protozoan parasite T. gondii can cause severe and potentially fatal cerebral and ocular disease, especially in immunocompromised individuals. The anticoccidial ionophore drug monensin has been shown to have anti-Toxoplasma gondii properties. However, the comprehensive molecular mechanisms that underlie the effect of monensin on T. gondii are still largely unknown. We hypothesized that analysis of T. gondii transcriptional changes induced by monensin treatment can reveal new aspects of the mechanism of action of monensin against T. gondii.Methods: Porcine kidney (PK)-15 cells were infected with tachyzoites of T. gondii RH strain. Three hours post-infection, PK-15 cells were treated with 0.1 μM monensin, while control cells were treated with medium only. PK-15 cells containing intracellular tachyzoites were harvested at 6 and 24 h post-treatment, and the transcriptomic profiles of T. gondii-infected PK-15 cells were examined using high-throughput RNA sequencing (RNA-seq). Quantitative real-time PCR was used to verify the expression of 15 differentially expressed genes (DEGs) identified by RNA-seq analysis.Results: A total of 4868 downregulated genes and three upregulated genes were identified in monensin-treated T. gondii, indicating that most of T. gondii genes were suppressed by monensin. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of T. gondii DEGs showed that T. gondii metabolic and cellular pathways were significantly downregulated. Spliceosome, ribosome, and protein processing in endoplasmic reticulum were the top three most significantly enriched pathways out of the 30 highly enriched pathways detected in T. gondii. This result suggests that monensin, via down-regulation of protein biosynthesis in T. gondii, can limit the parasite growth and proliferation. Conclusions:Our findings provide a comprehensive insight into T. gondii genes and pathways with altered expression following monensin treatment. These data can be further explored to achieve better understanding of the specific mechanism of action of monensin against T. gondii.

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Section: Discussionmentioning

confidence: 99%

“…Toxoplasma gondii is one of the most successful opportunistic pathogens and has a wide range of intermediate hosts [1,2]. This prolific parasite is estimated to cause latent infection in a third of the global human population [3].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional changes in Toxoplasma gondii in response to treatment with monensin

Zhai

Elsheikha

et al. 2020

Parasites Vectors

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“…Combination therapy is currently the standard of care against acute toxoplasmosis (7). First line drug combinations are pyrimethamine+sulfadiazine, which target two independent steps of the folic acid synthesis pathway, depriving the parasites of purines.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Guanabenz Combination Therapy Against Chronic Toxoplasmosis Across Multiple Mouse Strains

Martynowicz¹,

Doggett²,

Sullivan³

2020

Preprint

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21Toxoplasma gondii, an obligate intracellular parasite that can cause life-threatening 22 acute disease, differentiates into a quiescent cyst stage to establish lifelong chronic infections in 23 animal hosts, including humans. This tissue cyst reservoir, which can reactivate into an acute 24 infection, is currently refractory to clinically available therapeutics. Recently, we and others have 25 discovered drugs capable of significantly reducing brain cyst burden in latently infected mice, 26 but not to undetectable levels. In this study, we examined the use of novel combination 27 therapies possessing multiple mechanisms of action in mouse models of latent toxoplasmosis. 28Our drug regimens included combinations of pyrimethamine, clindamycin, guanabenz, and 29 endochin-like quinolones (ELQs), and were administered to two different mouse strains in an 30 attempt to eradicate brain tissue cysts. We observed mouse strain-dependent effects with these 31 drug treatments: pyrimethamine + guanabenz showed synergistic efficacy in C57BL/6 mice, yet 32 did not improve upon guanabenz monotherapy in BALB/c mice. Contrary to promising in vitro 33 results demonstrating toxicity to bradyzoites, we observed an antagonistic effect between 34 guanabenz + ELQ-334 in vivo. While we were unable to completely eliminate brain cyst burden, 35we found that a combination treatment of ELQ-334 + pyrimethamine impressively reduced brain 36 cysts to 95% in C57BL/6 mice, which approaches the limit of detection. These analyses 37 highlight the importance of evaluating anti-infective drugs in multiple mouse strains and will help 38 inform further preclinical cocktail therapy studies designed to treat chronic toxoplasmosis. 39 40

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“…More severe disease has been reported in some regions of South America where infections are associated with ocular disease in otherwise healthy individuals (9). Toxoplasmosis is typically treated by anti-folates using a combination of pyrimethamine-sulfadiazine or trimethoprim-sulfamethoxazole, although pyrimethamine has also been used in combination with clindamycin, azithromycin, and atovaquone (also used as monotherapy) (10). With the exception of congenital infection, infections are not commonly transferred from human-to-human, so emergence of drug resistance is rarely a problem.…”

Section: Introductionmentioning

confidence: 99%

Evolution of resistance in vitro reveals a novel mechanism of artemisinin activity in Toxoplasma gondii

Rozenberg

Luth

Winzeler

et al. 2019

Preprint

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250)Artemisinins are effective against a variety of parasites and provide the first line of treatment for malaria. Laboratory studies have identified several mechanisms for artemisinin resistance in Plasmodium falciparum, including mutations in Kelch13 that are associated with delayed clearance in some clinical isolates, although other mechanisms are likely involved. To explore other potential mechanisms of resistance in parasites, we took advantage of the genetic tractability of T. gondii, a related apicomplexan parasite that shows moderate sensitivity to artemisinin. Resistant populations of T. gondii were selected by culture in increasing drug concentrations and whole genome sequencing identified several non-conservative point mutations that emerged in the population and were fixed over time. Genome editing using CRISPR/Cas9 was used to introduce point mutations conferring amino acids changes in a serine protease homologous to DegP and a serine/threonine protein kinase of unknown function. Single and double mutations conferred a competitive advantage over wild type parasites in the presence of drug, despite not changing EC 50 values. Additionally, the evolved resistant lines showed dramatic amplification of the mitochondrial genome, including genes encoding cytochrome b and cytochrome oxidase I. Consistent with prior studies in yeast and mammalian tumor cells that implicate the mitochondrion as a target of artemisinins, treatment of wild type parasites with artemisinin decreased mitochondrial membrane potential, and resistant parasites showed altered morphology and decreased membrane potential. These findings extend the repertoire of mutations associated with artemisinin resistance and suggest that the mitochondrion may be an important target of inhibition in T. gondii. Significance (120)Artemisinins provide important therapeutic agents for treatment of malaria and have potential for use in other infections and in cancer. Their use is threatened by the potential for resistance development, so understanding their mechanism of action and identifying genetic changes that alter sensitivity are important for improving clinical outcomes. Our findings suggest that mutations in novel targets can contribute to the emergence of parasites with increased tolerance to artemisinin treatment and that such mutations can confer a fitness advantage even in the absence of a notable shift in EC 50 . Our findings also support the idea that inhibition of mitochondrial function may be an important target in T.gondii, as previously suggested by studies in yeast and human cancer cells.P. falciparum. The ART mechanism of action against tumor cells is also uncertain, but has been linked to oxidative stress, DNA damage, decreased cell replication, and activation of cell death pathways including apoptosis (41, 42). Studies in Baker's yeast (S. cerevisiae) implicate the mitochondria as a target of ART, and consistent with this model, growth on fermentable carbon sources results in genome sequence, as its assembly has been complicated by th...

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Treatment of Toxoplasmosis: Historical Perspective, Animal Models, and Current Clinical Practice

Cited by 323 publications

References 260 publications

Transcriptional changes in Toxoplasma gondii in response to treatment with monensin

Transcriptional changes in Toxoplasma gondii in response to treatment with monensin

Efficacy of Guanabenz Combination Therapy Against Chronic Toxoplasmosis Across Multiple Mouse Strains

Evolution of resistance in vitro reveals a novel mechanism of artemisinin activity in Toxoplasma gondii

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