Enzymes of energy metabolism in the bradyzoites and tachyzoites of<i>Toxoplasma gondii</i>

Denton, Helen; Roberts, Craig W.; Alexander, James; Thong, Kam-Wah; Coombs, Graham H.

doi:10.1111/j.1574-6968.1996.tb08090.x

Cited by 109 publications

(25 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another interesting group of chronic infection DEGs are those involved in glycolysis: glucose-6-phosphate isomerase, pyruvate kinase, lactate dehydrogenase 2, and glucosephosphate mutase. Previous data showed that tachyzoites and bradyzoites use the glycolytic pathway differently with lactate dehydrogenase 2 and pyruvate kinase being up-regulated during the bradyzoite stage [33, 34]. Our data shows that in addition to these two previously described bradyzoite-specific glycolytic enzymes, glucose-6-phosphate isomerase and glucosephosphate mutase are also more abundant in chronic vs acute infection.…”

Section: Resultssupporting

confidence: 60%

Dual transcriptional profiling of mice and Toxoplasma gondii during acute and chronic infection

2014

View full text Add to dashboard Cite

BackgroundThe obligate intracellular parasite Toxoplasma gondii establishes a life-long chronic infection within any warm-blooded host. After ingestion of an encysted parasite, T. gondii disseminates throughout the body as a rapidly replicating form during acute infection. Over time and after stimulation of the host immune response, T. gondii differentiates into a slow growing, cyst form that is the hallmark of chronic infection. Global transcriptome analysis of both host and parasite during the establishment of chronic T. gondii infection has not yet been performed. Here, we conducted a dual RNA-seq analysis of T. gondii and its rodent host to better understand host and parasite responses during acute and chronic infection.ResultsWe obtained nearly one billion paired-end RNA sequences from the forebrains of uninfected, acutely and chronically infected mice, then aligned them to the genomic reference files of both T. gondii and Mus musculus. Gene ontology (GO) analysis of the 100 most highly expressed T. gondii genes showed less than half were shared between acute and chronic infection. The majority of the highly expressed genes common in both acute and chronic infection were involved in transcription and translation, underscoring that parasites in both stages are actively synthesizing proteins. Similarly, most of the T. gondii genes highly expressed during chronic infection were involved in metabolic processes, again highlighting the activity of the cyst stage at 28 days post-infection. Comparative analyses of host genes using uninfected forebrain revealed over twice as many immune regulatory genes were more abundant during chronic infection compared to acute. This demonstrates the influence of parasite development on host gene transcription as well as the influence of the host environment on parasite gene transcription.ConclusionsRNA-seq is a valuable tool to simultaneously analyze host and microbe transcriptomes. Our data shows that T. gondii is metabolically active and synthesizing proteins at 28 days post-infection and that a distinct subset of host genes associated with the immune response are more abundant specifically during chronic infection. These data suggest host and pathogen interplay is still present during chronic infection and provides novel T. gondii targets for future drug and vaccine development.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-806) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultssupporting

confidence: 60%

Dual transcriptional profiling of mice and Toxoplasma gondii during acute and chronic infection

2014

View full text Add to dashboard Cite

show abstract

“…Glycolytic intermediates were generally more abundant in the infection metabolome, apart from 48 HPI when many were depleted. This result is expected given previous work demonstrating a highly active T. gondii glycolytic pathway and the energetic burden of infection on host cells [2,4,7,31]. Host hexose kinase (HK) and pyruvate kinase (PK) were transcriptionally upregulated in infected cells at every time point during infection (Table 1) and were highly transcribed throughout infection in T. gondii with FPKM values regularly at or above 50 (Table 2).…”

Section: Glycolysis Increasessupporting

confidence: 65%

Dual metabolomic profiling uncovers Toxoplasma manipulation of the host metabolome and the discovery of a novel parasite metabolic capability

et al. 2020

View full text Add to dashboard Cite

The obligate intracellular parasite Toxoplasma gondii is auxotrophic for several key metabolites and must scavenge these from the host. It is unclear how T. gondii manipulates host metabolism to support its overall growth rate and non-essential metabolites. To investigate this question, we measured changes in the joint host-parasite metabolome over a time course of infection. Host and parasite transcriptomes were simultaneously generated to determine potential changes in expression of metabolic enzymes. T. gondii infection changed metabolite abundance in multiple metabolic pathways, including the tricarboxylic acid cycle, the pentose phosphate pathway, glycolysis, amino acid synthesis, and nucleotide metabolism. Our analysis indicated that changes in some pathways, such as the tricarboxylic acid cycle, were mirrored by changes in parasite transcription, while changes in others, like the pentose phosphate pathway, were paired with changes in both the host and parasite transcriptomes. Further experiments led to the discovery of a T. gondii enzyme, sedoheptulose bisphosphatase, which funnels carbon from glycolysis into the pentose phosphate pathway through an energetically driven dephosphorylation reaction. This additional route for ribose synthesis appears to resolve the conflict between the T. gondii tricarboxylic acid cycle and pentose phosphate pathway, which are both NADP+ dependent. Sedoheptulose bisphosphatase represents a novel step in T. gondii central carbon metabolism that allows T. gondii to energetically-drive ribose synthesis without using NADP+.

show abstract

“…Mature bradyzoites are adapted for lifelong persistence in their hosts and exhibit an extreme reduction in growth rate until complete cell cycle arrest (25), with the glycolytic pathway appearing as their main source of energy. In contrast, tachyzoites, which are present during the acute phase of disease, are characterized by a rapid doubling time of 6 to 8 h, indicating that this phase is an effective pathway for the acquisition of nutrients and energy metabolism (26) and for the use of the tricarboxylic acid cycle associated with the respiratory chain to obtain energy (27) (28).…”

Section: Discussionmentioning

confidence: 99%

Effect of 3-Bromopyruvate and Atovaquone on Infection during In Vitro Interaction of Toxoplasma gondii and LLC-MK2 Cells

Lima

Seabra

Carneiro

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

bToxoplasma gondii infection can be severe during pregnancy and in immunocompromised patients. Current therapies for toxoplasmosis are restricted to tachyzoites and have little or no effect on bradyzoites, which are maintained in tissue cysts. Consequently, new therapeutic alternatives have been proposed as the use of atovaquone has demonstrated partial efficacy against tachyzoites and bradyzoites. This work studies the effect of 3-bromopyruvate (3-BrPA), a compound that is being tested against cancer cells, on the infection of LLC-MK2 cells with T. gondii tachyzoites, RH strain. No effect of 3-BrPA on host cell proliferation or viability was observed, but it inhibited the proliferation of T. gondii. The incubation of cultures with lectin Dolichos biflorus agglutinin (DBA) showed the development of cystogenesis, and an ultrastructural analysis of parasite intracellular development confirmed morphological characteristics commonly found in tissue cysts. Moreover, the presence of degraded parasites and the influence of 3-BrPA on endodyogeny were observed. Infected cultures were alternatively treated with a combination of this compound plus atovaquone. This resulted in a 73% reduction in intracellular parasites after 24 h of treatment and a 71% reduction after 48 h; cyst wall formation did not occur in these cultures. Therefore, we conclude that the use of 3-BrPA may serve as an important tool for the study of (i) in vitro cystogenesis; (ii) parasite metabolism, requiring a deeper understanding of the target of action of this compound on T. gondii; (iii) the alternative parasite metabolic pathways; and (iv) the molecular/cellular mechanisms that trigger parasite death.T oxoplasma gondii is an obligatory intracellular protozoan causative agent of toxoplasmosis that has a life cycle involving members of the family Felidae as definitive hosts and warmblooded animals, including humans, as intermediate hosts (1). The development of toxoplasmosis involves asexual replication. This gives rise to tachyzoites that are characterized by rapid growth during acute infection and bradyzoites found within tissue cysts, which slowly multiply and are responsible for the chronic phase of toxoplasmosis (2). In humans, the disease is typically asymptomatic; however, it is severe in immunocompromised individuals and congenital cases. For control of the infection, the most widely used therapy has been a combination of pyrimethamine and sulfadiazine (3), but this combination is commonly associated with several limitations due to adverse reactions, hypersensitivity, and hematologic toxicity (4). Although this combination is the treatment of choice and is used as prophylaxis, some patients are intolerant to this scheme and require alternative therapies (5). Atovaquone, a hydroxyl-1,4-naphthoquinone with a broad spectrum of antiprotozoan activity, has been FDA approved for the treatment of toxoplasmosis. This compound has shown efficacy against tachyzoites in vitro and in vivo (6, 7) and has a synergistic effect with clindamycin in acute muri...

show abstract

Enzymes of energy metabolism in the bradyzoites and tachyzoites ofToxoplasma gondii

Cited by 109 publications

References 14 publications

Dual transcriptional profiling of mice and Toxoplasma gondii during acute and chronic infection

Dual transcriptional profiling of mice and Toxoplasma gondii during acute and chronic infection

Dual metabolomic profiling uncovers Toxoplasma manipulation of the host metabolome and the discovery of a novel parasite metabolic capability

Effect of 3-Bromopyruvate and Atovaquone on Infection during In Vitro Interaction of Toxoplasma gondii and LLC-MK2 Cells

Contact Info

Product

Resources

About