scholarly journals Anti-Toxoplasma gondii Effects of a Novel Spider Peptide XYP1 In Vitro and In Vivo

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 934
Author(s):  
Yuan Liu ◽  
Yaqin Tang ◽  
Xing Tang ◽  
Mengqi Wu ◽  
Shengjie Hou ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Toxoplasma Gondii ◽  
Venom Gland ◽  
Host Cells ◽  
Drug Candidate ◽  
Membrane Perforation ◽  
Associated Proteins ◽  
Low Cytotoxicity

Toxoplasmosis, caused by an obligate intracellular parasite Toxoplasma gondii, is one of the most prevalent zoonoses worldwide. Treatments for this disease by traditional drugs have shown numerous side effects, thus effective alternative anti-Toxoplasma strategies or drugs are urgently needed. In this study, a novel spider peptide, XYP1, was identified from the cDNA library of the venom gland of the spider Lycosa coelestis. Our results showed that XYP1 has potent anti-Toxoplasma activity in vitro and in vivo. Specifically, treatment with XYP1 significantly inhibited the viability, invasion and proliferation of tachyzoites with low cytotoxicity (IC50 = 38.79 μΜ) on human host cells, and increased the survival rate of mice acutely infected with T. gondii. Next, scanning electron microscopy, transmission electron microscopy and RNA sequencing were employed to further explore the functional mechanism of XYP1, and the results indicated that XYP1 causes membrane perforation, swelling and disruption of tachyzoites, which could be closely associated with differential expression of several membrane-associated proteins including HSP29. In conclusion, XYP1 may be a promising new drug candidate for the treatment of toxoplasmosis.

scholarly journals ROP18-Mediated Transcriptional Reprogramming of HEK293T Cell Reveals New Roles of ROP18 in the Interplay Between Toxoplasma gondii and the Host Cell

2020 ◽  
Vol 10 ◽  
Author(s):  
Jie-Xi Li ◽  
Jun-Jun He ◽  
Hany M. Elsheikha ◽  
Jun Ma ◽  
Xiao-Pei Xu ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Hek293t Cell ◽  
Effector Proteins ◽  
Host Cells ◽  
Pathway Enrichment Analysis ◽  
Type I ◽  
Human Embryonic Kidney Cells ◽  
Pathway Enrichment

Toxoplasma gondii secretes a number of virulence-related effector proteins, such as the rhoptry protein 18 (ROP18). To further broaden our understanding of the molecular functions of ROP18, we examined the transcriptional response of human embryonic kidney cells (HEK293T) to ROP18 of type I T. gondii RH strain. Using RNA-sequencing, we compared the transcriptome of ROP18-expressing HEK293T cells to control HEK293T cells. Our analysis revealed that ROP18 altered the expression of 750 genes (467 upregulated genes and 283 downregulated genes) in HEK293T cells. Gene ontology (GO) and pathway enrichment analyses showed that differentially expressed genes (DEGs) were significantly enriched in extracellular matrix– and immune–related GO terms and pathways. KEGG pathway enrichment analysis revealed that DEGs were involved in several disease-related pathways, such as nervous system diseases and eye disease. ROP18 significantly increased the alternative splicing pattern “retained intron” and altered the expression of 144 transcription factors (TFs). These results provide new insight into how ROP18 may influence biological processes in the host cells via altering the expression of genes, TFs, and pathways. More in vitro and in vivo studies are required to substantiate these findings.

scholarly journals The ketolide antibiotics HMR 3647 and HMR 3004 are active against Toxoplasma gondii in vitro and in murine models of infection.

1997 ◽  
Vol 41 (10) ◽  
pp. 2137-2140 ◽  
Author(s):  
F G Araujo ◽  
A A Khan ◽  
T L Slifer ◽  
A Bryskier ◽  
J S Remington
Keyword(s):  
Toxoplasma Gondii ◽  
Protozoan Parasite ◽  
Host Cells ◽  
Resistant Bacteria ◽  
New Class ◽  
Human Foreskin Fibroblasts ◽  
Significant Toxicity ◽  
Different Strains

Ketolides are a new class of macrolide antibiotics that have been shown to be active against a variety of bacteria including macrolide-resistant bacteria and mycobacteria. We examined two ketolides, HMR 3647 and HMR 3004, for their in vitro and in vivo activities against the protozoan parasite Toxoplasma gondii. In vitro, both ketolides at concentrations as low as 0.05 microg/ml markedly inhibited replication of tachyzoites of the RH strain within human foreskin fibroblasts. HMR 3004 demonstrated some toxicity for host cells after they were exposed to 5 microg of the drug per ml for 72 h. In contrast, HMR 3647 did not show any significant toxicity even at concentrations as high as 25 microg/ml. In vivo, both ketolides provided remarkable protection against death in mice lethally infected intraperitoneally with tachyzoites of the RH strain or orally with tissue cysts of the C56 strain of T. gondii. A dosage of 100 mg of HMR 3647 per kg of body weight per day administered for 10 days protected 50% of mice infected with tachyzoites. The same dosage of HMR 3004 protected 100% of the mice. In mice infected with cysts, a dosage of 30 mg of HMR 3647 per kg per day protected 100% of the mice, whereas a dosage of 40 mg of HMR 3004 per kg per day protected 75% of the mice. These results demonstrate that HMR 3647 and HMR 3004 possess excellent activities against two different strains of T. gondii and may be useful for the treatment of toxoplasmosis in humans.

scholarly journals The inhibitory effect of cromolyn sodium and ketotifen on Toxoplasma gondii entrance into host cells in vitro and in vivo

2014 ◽  
Vol 40 (3) ◽  
pp. 1001-1005 ◽  
Author(s):  
Fatemeh Rezaei ◽  
Mohammad Ali Ebrahimzadeh ◽  
Ahmad Daryani ◽  
Mehdi Sharif ◽  
Ehsan Ahmadpour ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Inhibitory Effect ◽  
Cromolyn Sodium ◽  
Host Cells

scholarly journals Actin depolymerizing factor controls actin turnover and gliding motility in Toxoplasma gondii

2011 ◽  
Vol 22 (8) ◽  
pp. 1290-1299 ◽  
Author(s):  
Simren Mehta ◽  
L. David Sibley
Keyword(s):  
Toxoplasma Gondii ◽  
Actin Filaments ◽  
Gliding Motility ◽  
Conditional Knockout ◽  
Host Cells ◽  
Actin Binding ◽  
Actin Depolymerizing Factor

Apicomplexan parasites rely on actin-based gliding motility to move across the substratum, cross biological barriers, and invade their host cells. Gliding motility depends on polymerization of parasite actin filaments, yet ∼98% of actin is nonfilamentous in resting parasites. Previous studies suggest that the lack of actin filaments in the parasite is due to inherent instability, leaving uncertain the role of actin-binding proteins in controlling dynamics. We have previously shown that the single allele of Toxoplasma gondii actin depolymerizing factor (TgADF) has strong actin monomer–sequestering and weak filament-severing activities in vitro. Here we used a conditional knockout strategy to investigate the role of TgADF in vivo. Suppression of TgADF led to accumulation of actin-rich filaments that were detected by immunofluorescence and electron microscopy. Parasites deficient in TgADF showed reduced speed of motility, increased aberrant patterns of motion, and inhibition of sustained helical gliding. Lack of TgADF also led to severe defects in entry and egress from host cells, thus blocking infection in vitro. These studies establish that the absence of stable actin structures in the parasite are not simply the result of intrinsic instability, but that TgADF is required for the rapid turnover of parasite actin filaments, gliding motility, and cell invasion.

scholarly journals p47 GTPases Regulate Toxoplasma gondii Survival in Activated Macrophages

2005 ◽  
Vol 73 (6) ◽  
pp. 3278-3286 ◽  
Author(s):  
Barbara A. Butcher ◽  
Robert I. Greene ◽  
Stanley C. Henry ◽  
Kimberly L. Annecharico ◽  
J. Brice Weinberg ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Acute Infection ◽  
Host Cells ◽  
Intracellular Growth ◽  
Latex Beads ◽  
Cellular Factors ◽  
Ifn Γ ◽  
Normal Inhibition

ABSTRACT The cytokine gamma interferon (IFN-γ) is critical for resistance to Toxoplasma gondii. IFN-γ strongly activates macrophages and nonphagocytic host cells to limit intracellular growth of T. gondii; however, the cellular factors that are required for this effect are largely unknown. We have shown previously that IGTP and LRG-47, members of the IFN-γ-regulated family of p47 GTPases, are required for resistance to acute T. gondii infections in vivo. In contrast, IRG-47, another member of this family, is not required. In the present work, we addressed whether these GTPases are required for IFN-γ-induced suppression of T. gondii growth in macrophages in vitro. Bone marrow macrophages that lacked IGTP or LRG-47 displayed greatly attenuated IFN-γ-induced inhibition of T. gondii growth, while macrophages that lacked IRG-47 displayed normal inhibition. Thus, the ability of the p47 GTPases to limit acute infection in vivo correlated with their ability to suppress intracellular growth in macrophages in vitro. Using confocal microscopy and sucrose density fractionation, we demonstrated that IGTP largely colocalizes with endoplasmic reticulum markers, while LRG-47 was mainly restricted to the Golgi. Although both IGTP and LRG-47 localized to vacuoles containing latex beads, neither protein localized to vacuoles containing live T. gondii. These results suggest that IGTP and LRG-47 are able to regulate host resistance to acute T. gondii infections through their ability to inhibit parasite growth within the macrophage.

scholarly journals Rifapentine is active in vitro and in vivo against Toxoplasma gondii.

1996 ◽  
Vol 40 (6) ◽  
pp. 1335-1337 ◽  
Author(s):  
F G Araujo ◽  
A A Khan ◽  
J S Remington
Keyword(s):  
Toxoplasma Gondii ◽  
Protozoan Parasite ◽  
Host Cells ◽  
Intracellular Replication ◽  
Degree Of Protection

Rifapentine, a derivative of rifamycin, was examined for its in vitro and in vivo activities against the protozoan parasite Toxoplasma gondii. The drug inhibited the intracellular replication of parasites and was not cytotoxic for the host cells at inhibitory concentrations. Mice infected either intraperitoneally with tachyzoites of the RH strain or orally with tissue cysts of the C56 strain were protected against death by treatment with rifapentine. The degree of protection was similar to that induced by atovaquone and apparently higher than that induced by rifabutin. Rifapentine may be a useful drug for the treatment of toxoplasmosis in immunocompromised individuals.

scholarly journals AMA1-Deficient Toxoplasma gondii Parasites Transiently Colonize Mice and Trigger an Innate Immune Response That Leads to Long-Lasting Protective Immunity

2015 ◽  
Vol 83 (6) ◽  
pp. 2475-2486 ◽  
Author(s):  
Vanessa Lagal ◽  
Márcia Dinis ◽  
Dominique Cannella ◽  
Daniel Bargieri ◽  
Virginie Gonzalez ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Distinct Type ◽  
Genetically Engineered ◽  
Host Cells ◽  
Type I ◽  
Content Type ◽  
Apical Membrane Antigen 1 ◽  
Immunocompromised Mice

The apical membrane antigen 1 (AMA1) protein was believed to be essential for the perpetuation of two Apicomplexa parasite genera,PlasmodiumandToxoplasma, until we genetically engineered viable parasites lackingAMA1. The reduction in invasiveness of theToxoplasma gondiiRH-AMA1 knockout (RH-AMA1KO) tachyzoite population,in vitro, raised key questions about the outcome associated with these tachyzoites once inoculated in the peritoneal cavity of mice. In this study, we used AMNIS technology to simultaneously quantify and image the parasitic process driven by AMA1KOtachyzoites. We report their ability to colonize and multiply in mesothelial cells and in both resident and recruited leukocytes. While the RH-AMA1KOpopulation amplification is rapidly lethal in immunocompromised mice, it is controlled in immunocompetent hosts, where immune cells in combination sense parasites and secrete proinflammatory cytokines. This innate response further leads to a long-lasting status immunoprotective against a secondary challenge by high inocula of the homologous type I or a distinct type IIT. gondiigenotypes. While AMA1 is definitively not an essential protein for tachyzoite entry and multiplication in host cells, it clearly assists the expansion of parasite populationin vivo.

scholarly journals Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hana Bavlovič Piskáčková ◽  
Hana Jansová ◽  
Jan Kubeš ◽  
Galina Karabanovich ◽  
Nela Váňová ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Aqueous Solubility ◽  
Water Soluble ◽  
Drug Candidate ◽  
Anthracycline Cardiotoxicity ◽  
Cardioprotective Effects ◽  
Low Cytotoxicity ◽  
Anthracycline Toxicity

AbstractThe bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs). Based on the obtained results, the bis(2-aminoacetoxymethyl)-type prodrug GK-667 was selected for advanced investigations due to its straightforward synthesis, sufficient solubility, low cytotoxicity and favorable ICRF-193 release. Upon administration of GK-667 to NVCMs, the released ICRF-193 penetrated well into the cells, reached sufficient intracellular concentrations and provided effective cytoprotection against anthracycline toxicity. The pharmacokinetics of the prodrug, ICRF-193 and its rings-opened metabolite was estimated in vivo after administration of GK-667 to rabbits. The plasma concentrations of ICRF-193 reached were found to be adequate to achieve cardioprotective effects in vivo. Hence, GK-667 was demonstrated to be a pharmaceutically acceptable prodrug of ICRF-193 and a promising drug candidate for further evaluation as a potential cardioprotectant against chronic anthracycline toxicity.

In vitro activity of the polyether ionophorous antibiotic monensin against the cyst form of Toxoplasma gondii

Parasitology ◽  
2000 ◽  
Vol 121 (4) ◽  
pp. 359-365 ◽  
Author(s):  
S. COUZINET ◽  
J. F. DUBREMETZ ◽  
D. BUZONI-GATEL ◽  
G. JEMINET ◽  
G. PRENSIER
Keyword(s):  
Electron Microscopy ◽  
Toxoplasma Gondii ◽  
In Vitro Activity ◽  
Cyst Form ◽  
Drug Concentrations ◽  
Electron Microscopy Analysis ◽  
Microscopy Analysis ◽  
Cytological Alterations

We have studied the activity of the polyether ionophorous antibiotic monensin against the cyst form (bradyzoite) of Toxoplasma gondii. The experiments were conducted in vitro using 2 methods; cysts produced either in mice or in cell culture were exposed to monensin in vitro, and the infectivity of the parasites was then assessed in vivo or in vitro. The data obtained from these 2 systems of evaluation showed that monensin inhibits the infectivity and the viability of the bradyzoites. Its activity was time and concentration dependent. The first effects were observed at very low drug concentrations (i.e. 0·0001 μg/ml). Immunofluorescence and electron microscopy analysis showed significant cytological alterations of the monensin-treated bradyzoites: they were swollen, had a large number of vacuoles in their cytoplasm and were found lysed at higher concentrations in ionophore.

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