Orally Bioavailable Endochin-like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts

2020 ◽  
Author(s):  
Zhang-He Goh
Keyword(s):  
Toxoplasma Gondii ◽  
Orally Bioavailable ◽  
Brain Cysts ◽  
Ester Prodrug

scholarly journals Molecular characterization of Toxoplasma gondii isolates from free-range chickens reveals new genotypes in Goiânia, Goiás, Brazil

2021 ◽  
Vol 30 (2) ◽  
Author(s):  
Hanstter Hallison Alves Rezende ◽  
Jaqueline Ataíde Silva Lima da Igreja ◽  
Antônio Roberto Gomes-Júnior ◽  
Jade de Oliveira Melo ◽  
João Luís Garcia ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Metropolitan Area ◽  
Seroprevalence Rate ◽  
Free Range ◽  
Low Genetic Diversity ◽  
Pcr Rflp ◽  
Peptic Digestion ◽  
Brain Cysts ◽  
Genotypic Characteristics

Abstract The aim of this study was to evaluate the genotypic characteristics of Toxoplasma gondii isolated from free-range chickens in the metropolitan area of Goiânia, Goiás, in Brazil’s central-west region. The seroprevalence rate was found to be 96%, according to an indirect hemagglutination assay. Brain and heart samples were processed by peptic digestion for a mice bioassay. The tissues were homogenized and the resulting samples were subjected to polymerase chain reaction (PCR), which revealed that 64% of them contained the parasite's DNA. The mice bioassay revealed 15 isolates, 8 of them tachyzoites isolates from the peritoneal lavage and 7 from brain cysts. T. gondii genotypes were determined through PCR-RFLP, using the following markers: SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, alt. SAG2, Apico and CS3. Three genotypes were identified, inclued ToxoDB #65, and the other two are not yet described in the literature. Hence, we conclude that the isolates obtained from the metropolitan area of Goiânia showed relatively low genetic diversity.

Corticosteroids Opportunist Higher Toxoplasma gondii Brain Cysts in Latent Infected Mice

2015 ◽  
Vol 11 (4) ◽  
pp. 169-176 ◽  
Author(s):  
Hasan A. Elfadaly ◽  
Mohey A. Hassanain ◽  
Raafat M. Shaapan ◽  
Nawal A. Hassanain ◽  
Ashraaf M. Barakat
Keyword(s):  
Toxoplasma Gondii ◽  
Brain Cysts

scholarly journals RHΔgra17Δnpt1 Strain of Toxoplasma gondii Elicits Protective Immunity Against Acute, Chronic and Congenital Toxoplasmosis in Mice

2020 ◽  
Vol 8 (3) ◽  
pp. 352 ◽  
Author(s):  
Qin-Li Liang ◽  
Li-Xiu Sun ◽  
Hany M. Elsheikha ◽  
Xue-Zhen Cao ◽  
Lan-Bi Nie ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Cellular Response ◽  
Protective Efficacy ◽  
Interleukin 2 ◽  
Congenital Toxoplasmosis ◽  
Congenital Infection ◽  
Dense Granule ◽  
Lethal Challenge ◽  
Double Deletion ◽  
Brain Cysts

In the present study, a dense granule protein 17 (gra17) and novel putative transporter (npt1) double deletion mutant of Toxoplasma gondii RH strain was engineered. The protective efficacy of vaccination using RHΔgra17Δnpt1 tachyzoites against acute, chronic, and congenital toxoplasmosis was studied in a mouse model. Immunization using RHΔgra17Δnpt1 induced a strong humoral and cellular response, as indicated by the increased levels of anti-T. gondii specific IgG, interleukin 2 (IL-2), IL-10, IL-12, and interferon-gamma (IFN-γ). Vaccinated mice were protected against a lethal challenge dose (103 tachyzoites) of wild-type homologous (RH) strain and heterologous (PYS and TgC7) strains, as well as against 100 tissue cysts or oocysts of Pru strain. Vaccination also conferred protection against chronic infection with 10 tissue cysts or oocysts of Pru strain, where the numbers of brain cysts in the vaccinated mice were significantly reduced compared to those detected in the control (unvaccinated + infected) mice. In addition, vaccination protected against congenital infection with 10 T. gondii Pru oocysts (administered orally on day 5 of gestation) as shown by the increased litter size, survival rate and the bodyweight of pups born to vaccinated dams compared to those born to unvaccinated + infected dams. The brain cyst burden of vaccinated dams was significantly lower than that of unvaccinated dams infected with oocysts. Our data show that T. gondii RHΔgra17Δnpt1 mutant strain can protect mice against acute, chronic, and congenital toxoplasmosis by balancing inflammatory response with immunogenicity.

scholarly journals Orally Bioavailable Endochin-like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts

2020 ◽  
Author(s):  
J. Stone Doggett ◽  
Tracey Schultz ◽  
Alyssa J. Miller ◽  
Igor Bruzual ◽  
Sovitj Pou ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Oral Bioavailability ◽  
Oral Absorption ◽  
Therapeutic Potential ◽  
Plasma Concentrations ◽  
Intraperitoneal Administration ◽  
Maximum Plasma ◽  
Acute Toxoplasmosis ◽  
Ester Prodrug

AbstractToxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines for toxoplasmosis have high rates of adverse effects that interfere with therapeutic and prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors of Toxoplasma gondii proliferation in vitro and in animal models of acute and latent infection. ELQ-316, in particular, was found to be effective orally against acute toxoplasmosis in mice and highly selective for the T. gondii cytochrome b over the human cytochrome b. Despite oral efficacy, the high crystallinity of ELQ-316 limits oral absorption, plasma concentrations and therapeutic potential. A carbonate ester prodrug of ELQ-316, ELQ-334, was created to decrease crystallinity and increase oral bioavailability, which resulted in a six-fold increase in both Cmax (maximum plasma concentration) and AUC (area under the curve) of ELQ-316. The increased bioavailability of ELQ-316, when administered as ELQ-334, resulted in greater efficacy than the equivalent dose of ELQ-316 against acute toxoplasmosis and had similar efficacy against latent toxoplasmosis compared to intraperitoneal administration of ELQ-316. Carbonate ester prodrugs are a successful strategy to overcome the limited oral bioavailability of ELQs for the treatment of toxoplasmosis.

scholarly journals Significant Reduction of Brain Cysts Caused by Toxoplasma gondii after Treatment with Spiramycin Coadministered with Metronidazole in a Mouse Model of Chronic Toxoplasmosis

2012 ◽  
Vol 56 (4) ◽  
pp. 1762-1768 ◽  
Author(s):  
Wai Kit Chew ◽  
Ignacio Segarra ◽  
Stephen Ambu ◽  
Joon Wah Mak
Keyword(s):  
Toxoplasma Gondii ◽  
Vero Cells ◽  
Toxoplasmic Encephalitis ◽  
Combination Group ◽  
Control Group ◽  
Time Curve ◽  
Content Type ◽  
Brain Cysts ◽  
The Brain

ABSTRACTToxoplasma gondiiis a parasite that generates latent cysts in the brain; reactivation of these cysts may lead to fatal toxoplasmic encephalitis, for which treatment remains unsuccessful. We assessed spiramycin pharmacokinetics coadministered with metronidazole, the eradication of brain cysts and thein vitroreactivation. Male BALB/c mice were fed 1,000 tachyzoites orally to develop chronic toxoplasmosis. Four weeks later, infected mice underwent different treatments: (i) infected untreated mice (n= 9), which received vehicle only; (ii) a spiramycin-only group (n= 9), 400 mg/kg daily for 7 days; (iii) a metronidazole-only group (n= 9), 500 mg/kg daily for 7 days; and (iv) a combination group (n= 9), which received both spiramycin (400 mg/kg) and metronidazole (500 mg/kg) daily for 7 days. An uninfected control group (n= 10) was administered vehicle only. After treatment, the brain cysts were counted, brain homogenates were cultured in confluent Vero cells, and cysts and tachyzoites were counted after 1 week. Separately, pharmacokinetic profiles (plasma and brain) were assessed after a single dose of spiramycin (400 mg/kg), metronidazole (500 mg/kg), or both. Metronidazole treatment increased the brain spiramycin area under the concentration-time curve from 0 h to ∞ (AUC0–∞) by 67% without affecting its plasma disposition. Metronidazole plasma and brain AUC0–∞values were reduced 9 and 62%, respectively, after spiramycin coadministration. Enhanced spiramycin brain exposure after coadministration reduced brain cysts 15-fold (79 ± 23 for the combination treatment versus 1,198 ± 153 for the untreated control group [P< 0.05]) and 10-fold versus the spiramycin-only group (768 ± 125). Metronidazole alone showed no effect (1,028 ± 149). Tachyzoites were absent in the brain. Spiramycin reducedin vitroreactivation. Metronidazole increased spiramycin brain penetration, causing a significant reduction ofT. gondiibrain cysts, with potential clinical translatability for chronic toxoplasmosis treatment.

scholarly journals Recombinant GRA4 or ROP2 Protein Combined with Alum or the gra4 Gene Provides Partial Protection in Chronic Murine Models of Toxoplasmosis

2004 ◽  
Vol 11 (4) ◽  
pp. 704-710 ◽  
Author(s):  
Valentina Martin ◽  
Alicia Supanitsky ◽  
Pablo C. Echeverria ◽  
Silvana Litwin ◽  
Tamara Tanos ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Open Reading Frame ◽  
Interleukin 4 ◽  
Murine Models ◽  
Protective Level ◽  
Partial Protection ◽  
Reading Frame ◽  
C3h Mice ◽  
Entire Open Reading Frame ◽  
Brain Cysts

ABSTRACT The efficacy of vaccination with Toxoplasma gondii recombinant GRA4 (rGRA4) and ROP2 (rRPO2) proteins and a mix of both combined with alum were evaluated in C57BL/6 and C3H mice. In C57BL/6 mice, rGRA4 and rGRA4-rROP2 immunizations generated similar levels of immunoglobulin G1 (IgG1) and IgG2a isotypes against GRA4, whereas immunizations with rROP2 and the mix induced a predominant IgG1 production against ROP2. All groups of C3H vaccinated mice exhibited higher levels of IgG1 than IgG2a. rGRA4-stimulated splenocytes from vaccinated mice produced primarily gamma interferon while those stimulated with rROP2 produced interleukin-4. Challenge of rGRA4- or rGRA4-rROP2-vaccinated mice from both strains with ME49 cysts resulted in fewer brain cysts than the controls, whereas vaccination with rROP2 alone only conferred protection to C3H mice. Immunization with a plasmid carrying the entire open reading frame of GRA4 showed a protective level similar to that of rGRA4 combined with alum. These results suggest that GRA4 can be a good candidate for a multiantigen anti-T. gondii vaccine based on the use of alum as an adjuvant.

scholarly journals Bumped Kinase Inhibitor 1294 Treats Established Toxoplasma gondii Infection

2014 ◽  
Vol 58 (6) ◽  
pp. 3547-3549 ◽  
Author(s):  
J. Stone Doggett ◽  
Kayode K. Ojo ◽  
Erkang Fan ◽  
Dustin J. Maly ◽  
Wesley C. Van Voorhis
Keyword(s):  
Toxoplasma Gondii ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Content Type ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Orally Bioavailable ◽  
Toxoplasma Gondii Infection ◽  
Bumped Kinase Inhibitor

ABSTRACTToxoplasma gondiiis a unicellular parasite that causes severe brain and eye disease. Current drugs forT. gondiiare limited by toxicity. Bumped kinase inhibitors (BKIs) selectively inhibit calcium-dependent protein kinases of the apicomplexan pathogensT. gondii, cryptosporidia, and plasmodia. A lead anti-ToxoplasmaBKI, 1294, has been developed to be metabolically stable and orally bioavailable. Herein, we demonstrate the oral efficacy of 1294 against toxoplasmosisin vivo.

Toxoplasma gondii: Determination of the onset of chronic infection in mice and the in vitro reactivation of brain cysts

2012 ◽  
Vol 130 (1) ◽  
pp. 22-25 ◽  
Author(s):  
Wai Kit Chew ◽  
Mak Joon Wah ◽  
Stephen Ambu ◽  
Ignacio Segarra
Keyword(s):  
Toxoplasma Gondii ◽  
Chronic Infection ◽  
Brain Cysts

scholarly journals Computational image analysis reveals the structural complexity of Toxoplasma gondii tissue cysts

2020 ◽  
Author(s):  
Neda Bauman ◽  
Andjelija Ilić ◽  
Olivera Lijeskić ◽  
Aleksandra Uzelac ◽  
Ivana Klun ◽  
...  
Keyword(s):  
Image Analysis ◽  
Toxoplasma Gondii ◽  
Fractal Analysis ◽  
Structural Complexity ◽  
Particle Analysis ◽  
Particle Count ◽  
Novel Approach ◽  
Brain Cysts ◽  
Computational Image Analysis

AbstractToxoplasma gondii is an obligate intracellular parasite infecting up to one third of the human population. The central event in the pathogenesis of toxoplasmosis is the conversion of tachyzoites into encysted bradyzoites. A novel approach to analyze the structure of in vivo-derived tissue cysts may be the increasingly used computational image analysis. The objective of this study was to quantify the geometrical complexity of T. gondii cysts by morphological, particle, and fractal analysis, as well as to determine if and how it is impacted by parasite strain, cyst age, and host factors. Analyses were performed on 31 images of T. gondii brain cysts of four type-2 strains (the reference Me49 strain and three local isolates, named BGD1, BGD14, and BGD26) using ImageJ software package. The parameters of interest included diameter, circularity, relative particle count (RPC), fractal dimension (FD), lacunarity, and packing density (PD). Although cyst diameter varied widely, its negative correlation with RPC was observed. Circularity was remarkably close to 1, indicating that the shape of the brain cysts was a perfect circle. RPC, FD, and PD did not vary among cysts of different strains, age, and derived from mice of different genetic background. Conversely, lacunarity, which is a measure of heterogeneity, was significantly lower for BGD1 strain vs. all other strains, and higher for Me49 vs. BGD14 and BGD26, but did not differ among Me49 cysts of different age, and derived from genetically different mice. This study is the first application of fractal analysis in describing the structural complexity of T. gondii cysts. Despite all the differences among the analyzed cysts, most parameters remained conserved. Fractal analysis is a novel and widely accessible approach, which along with particle analysis may be applied to gain further insight into T. gondii cyst morphology.

scholarly journals Immunization with plasmid DNA expressing Heat Shock Protein 40 confers prophylactic protection against chronic Toxoplasma gondii infection in Kunming mice

Parasite ◽  
2018 ◽  
Vol 25 ◽  
pp. 37
Author(s):  
Zhong-Yuan Li ◽  
Jing Lu ◽  
Nian-Zhang Zhang ◽  
Hany M. Elsheikha ◽  
Jun-Ling Hou ◽  
...  
Keyword(s):  
Heat Shock ◽  
Toxoplasma Gondii ◽  
Heat Shock Protein ◽  
Control Mouse ◽  
Effective Vaccine ◽  
Type I ◽  
Immunogenic Proteins ◽  
Toxoplasma Gondii Infection ◽  
Brain Cysts ◽  
And Control

Toxoplasma gondii causes one of the most common protozoal diseases of humans and animals worldwide. With the aim of designing an effective vaccine against T. gondii infection, we examined the immunogenicity of a DNA vaccine expressing heat shock protein 40 (HSP40) against challenge with T. gondii (type I RH and type II Pru) strains in Kunming mice. The plasmid pVAX1-HSP40 was constructed and used to immunize mice by intramuscular injection for three sequential immunizations with two-week intervals. This immunization regimen significantly reduced parasite cyst burden in pVAX1-HSP40-immunized mice (1871.9 ± 142.3) compared with control mouse groups immunized with pVAX1 (3479.2 ± 204.4), phosphate buffered saline (3024.4 ± 212.8), or left untreated (3275.0 ± 179.8) as healthy controls (p < 0.01). However, immunization failed to protect mice against challenge with the virulent RH strain. There was a significant increase in T lymphocyte subclasses (CD3e+CD4+ T and CD3e+CD8a+ T lymphocytes) in splenic tissues in immunized mice compared with controls (p < 0.05). However, the level of antibodies, lymphocyte proliferation and concentration of cytokines (IFN-γ, IL-2, IL-4, IL-10 and IL-12p70) were not significantly different between immunized and control mouse groups (p < 0.05). These data indicate that pVAX1-HSP40 induced specific immune responses and achieved a significant reduction in the number of brain cysts in Pru-infected mice, and thus can be tested in future immunization studies along with plasmids containing other immunogenic proteins as a cocktail vaccine to fully abolish chronic toxoplasmosis.

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