Bradyzoite Development

Knoll, Laura J.; Tomita, Tadakimi; Weiss, Louis M.

doi:10.1016/b978-0-12-396481-6.00015-5

Cited by 17 publications

(24 citation statements)

References 194 publications

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“…The mechanisms and pathways underlying T . gondii differentiation remain poorly understood, despite numerous studies aimed at identifying differentiation effector and regulator genes [ 8 – 10 , 12 – 16 , 51 ]. An important recent advance was the identification of T .…”

Section: Discussionmentioning

confidence: 99%

“…Mutant parasite strains incapable of switching to the bradyzoite stage have been used to identify positive regulators of differentiation [ 10 , 12 ] and analyses of the epigenetic state of developmentally regulated genes [ 13 – 15 ] have shown that histone acetyltransferases, deacetylases and methyltransferases also affect expression of tachyzoite and bradyzoite-specific genes in vitro . These studies suggest that differentiation is a highly regulated process in which groups of genes are turned on and off in a specific temporal order [ 16 ]. Indeed, specific members of the ApiAP2 family of transcription factors are emerging as key regulators of the tachyzoite-to-bradyzoite developmental switch [ 17 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Yeast Three-Hybrid Screen Identifies TgBRADIN/GRA24 as a Negative Regulator of Toxoplasma gondii Bradyzoite Differentiation

et al. 2015

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Differentiation of the protozoan parasite Toxoplasma gondii into its latent bradyzoite stage is a key event in the parasite’s life cycle. Compound 2 is an imidazopyridine that was previously shown to inhibit the parasite lytic cycle, in part through inhibition of parasite cGMP-dependent protein kinase. We show here that Compound 2 can also enhance parasite differentiation, and we use yeast three-hybrid analysis to identify TgBRADIN/GRA24 as a parasite protein that interacts directly or indirectly with the compound. Disruption of the TgBRADIN/GRA24 gene leads to enhanced differentiation of the parasite, and the TgBRADIN/GRA24 knockout parasites show decreased susceptibility to the differentiation-enhancing effects of Compound 2. This study represents the first use of yeast three-hybrid analysis to study small-molecule mechanism of action in any pathogenic microorganism, and it identifies a previously unrecognized inhibitor of differentiation in T. gondii. A better understanding of the proteins and mechanisms regulating T. gondii differentiation will enable new approaches to preventing the establishment of chronic infection in this important human pathogen.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Yeast Three-Hybrid Screen Identifies TgBRADIN/GRA24 as a Negative Regulator of Toxoplasma gondii Bradyzoite Differentiation

et al. 2015

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“…The asexual cycle of T. gondii has two developmental stages: a rapidly replicating form called the tachyzoite and a slow-growing form called the bradyzoite that forms tissue cysts (2). Development of cysts (modified parasitophorous vacuoles containing bradyzoites) can occur in any warm-blooded animal.…”

Section: Introductionmentioning

confidence: 99%

“…Mucin-like domains are also present in yeast osmotic sensors such as Hkr1 and Msb2 (16, 17). CST1, which is found in the cyst wall of T. gondii , contains a mucin-like domain, and we have previously demonstrated that this domain is essential for cyst stability and that the absence of this domain alters the ultrastructure of the cyst wall (2). The mucin domain of CST1 is, therefore, a critical component of the cyst wall that is involved in essential functions of this structure.…”

Section: Introductionmentioning

confidence: 99%

Making Home Sweet and Sturdy:Toxoplasma gondiippGalNAc-Ts Glycosylate in Hierarchical Order and Confer Cyst Wall Rigidity

Tomita

Sugi

Yakubu

et al. 2017

mBio

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The protozoan intracellular parasite Toxoplasma gondii forms latent cysts in the central nervous system (CNS) and persists for the lifetime of the host. This cyst is cloaked with a glycosylated structure called the cyst wall. Previously, we demonstrated that a mucin-like glycoprotein, CST1, localizes to the cyst wall and confers structural rigidity on brain cysts in a mucin-like domain-dependent manner. The mucin-like domain of CST1 is composed of 20 units of threonine-rich tandem repeats that are O-GalNAc glycosylated. A family of enzymes termed polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts) initiates O-GalNAc glycosylation. To identify which isoforms of ppGalNAc-Ts are responsible for the glycosylation of the CST1 mucin-like domain and to evaluate the function of each ppGalNAc-T in the overall glycosylation of the cyst wall, all five ppGalNAc-T isoforms were deleted individually from the T. gondii genome. The ppGalNAc-T2 and -T3 deletion mutants produced various glycosylation defects on the cyst wall, implying that many cyst wall glycoproteins are glycosylated by T2 and T3. Both T2 and T3 glycosylate the CST1 mucin-like domain, and this glycosylation is necessary for CST1 to confer structural rigidity on the cyst wall. We established that T2 is required for the initial glycosylation of the mucin-like domain and that T3 is responsible for the sequential glycosylation on neighboring acceptor sites, demonstrating hierarchical glycosylation by two distinct initiating and filling-in ppGalNAc-Ts in an intact organism.

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“…Studies focused on the transcriptomes of tissue cysts (both in culture and in vivo) by necessity [17, 18•] presented a weighted average that masks the behavior of individual tissue cysts and by extension that of individual bradyzoites within them. The recurring differences, in cyst burden and size, were largely attributed to variations with the host response [19, 20] with little consideration to the fact that bradyzoites themselves may be considerably more dynamic than has been previously imagined [21••]. …”

Section: Introductionmentioning

confidence: 99%

Reexamining Chronic Toxoplasma gondii Infection: Surprising Activity for a “Dormant” Parasite

Sinai¹,

Watts

Dhara³

et al. 2016

Curr Clin Micro Rpt

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Purpose of Review Despite over a third of the world’s population being chronically infected with Toxoplasma gondii, little is known about this largely asymptomatic phase of infection. This stage is mediated in vivo by bradyzoites within tissue cysts. The absence of overt symptoms has been attributed to the dormancy of bradyzoites. In this review, we reexamine the conventional view of chronic toxoplasmosis in light of emerging evidence challenging both the nature of dormancy and the consequences of infection in the CNS. Recent Findings New and emerging data reveal a previously unrecognized level of physiological and replicative capacity of bradyzoites within tissue cysts. These findings have emerged in the context of a reexamination of the chronic infection in the brain that correlates with changes in neuronal architecture, neurochemistry, and behavior that suggest that the chronic infection is not without consequence. Summary The emerging data driven by the development of new approaches to study the progression of chronic toxoplasma infection reveals significant physiological and replicative capacity for what has been viewed as a dormant state. The emergence of bradyzoite and tissue cyst biology from what was viewed as a physiological “black box” offers exciting new areas for investigation with direct implications on the approaches to drug development targeting this drug-refractory state. In addition, new insights from studies on the neurobiology on chronic infection reveal a complex and dynamic interplay between the parasite, brain microenvironment, and the immune response that results in the detente that promotes the life-long persistence of the parasite in the host.

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Bradyzoite Development

Cited by 17 publications

References 194 publications

Yeast Three-Hybrid Screen Identifies TgBRADIN/GRA24 as a Negative Regulator of Toxoplasma gondii Bradyzoite Differentiation

Yeast Three-Hybrid Screen Identifies TgBRADIN/GRA24 as a Negative Regulator of Toxoplasma gondii Bradyzoite Differentiation

Making Home Sweet and Sturdy:Toxoplasma gondiippGalNAc-Ts Glycosylate in Hierarchical Order and Confer Cyst Wall Rigidity

Reexamining Chronic Toxoplasma gondii Infection: Surprising Activity for a “Dormant” Parasite

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