Early passage of Toxoplasma gondii across the blood–brain barrier

Ross, Emily C.; Olivera, Gabriela C.; Barragán, Antonio

doi:10.1016/j.pt.2022.02.003

Cited by 22 publications

(23 citation statements)

References 99 publications

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“…Molecular methods, such as using polymerase chain reaction (PCR) to detect T. gondii DNA, have proved to be simple, sensitive, reproducible, and cost-effective and have been applied in diverse clinical trials, including on animals and humans [ 19 ]. The number of tachyzoites and proportional parasite burden is much higher during Toxoplasma infection in peripheral organs, such as the lung parenchyma and liver parenchyma, compared with parenchymal organs [ 20 ]. The most common treatments for acute toxoplasmosis are sulfadiazine and pyrimethamine (Daraprim).…”

Section: Introductionmentioning

confidence: 99%

Wheat Germ Oil and Propolis Decrease Parasite Burden and Restore Marked Histopathological Changes in Liver and Lung in Mice with Chronic Toxoplasmosis

Barakat

Fadaly

Gareh

et al. 2022

Animals

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Toxoplasmosis is a parasitic zoonotic disease with a worldwide distribution. Its effects can be critical in immunocompromised patients. However, there is a limited availability of effective, low-toxicity drugs against this disease, particularly in its chronic form. The present study evaluated the effect of propolis and wheat germ oil (WGO) as safe, natural products to reduce Toxoplasma cysts in experimentally infected mice. For the experiment, five groups (10 mice per group) were examined: Group 1: negative control (noninfected, nontreated); Group 2: positive control (infected, nontreated); Group 3: infected and treated with WGO at a dose of 0.2 mg/1.5 mL per kg body weight/day; Group 4: infected and treated with 0.1 mL propolis extract/day; and Group 5: infected and treated with a combination of WGO and propolis at the same doses as Group 3 and 4. After the mice were sacrificed, liver and lung specimens underwent histopathological examination, and the parasite burden was investigated by parasitological methods and quantified using real-time polymerase chain reaction. Notably, the results showed a substantial decrease in parasitic burden in Group 5 compared to the control group. These results were further confirmed by molecular analysis and quantification of the DNA concentration of the Toxoplasma P29 gene after treatment in all tested samples. Furthermore, the combination of propolis and WGO restored all histopathological changes in the liver and lungs. Taken together, these findings provide remarkably promising evidence of the effects of the combination of WGO and propolis against chronic toxoplasmosis in mice.

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Section: Introductionmentioning

confidence: 99%

Wheat Germ Oil and Propolis Decrease Parasite Burden and Restore Marked Histopathological Changes in Liver and Lung in Mice with Chronic Toxoplasmosis

Barakat

Fadaly

Gareh

et al. 2022

Animals

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“…For example, ROP18 in type I (RH) has been shown to inhibit the host NF-κB pathway ( 51 ), which could further explain the reduced expression of ICAM-1. Moreover, the traits need to be confirmed in vivo in future studies despite the challenges that tracking infected leukocytes represent ( 12 , 17 ).…”

Section: Discussionmentioning

confidence: 99%

“…The present work provides novel insights in how T. gondii orchestrates the modulation of host cell adhesion, motility and transmigration of parasitised leukocytes across polarised endothelium. While leukocytes facilitate the systemic dissemination of T. gondii ( 15 , 16 ), their roles in mediating access to the brain parenchyma remain to be investigated ( 12 ). The infection of leukocytes by T. gondii may serve dual effects.…”

Section: Discussionmentioning

confidence: 99%

“…Yet, primary infection is often asymptomatic or accompanied by mild flu-like symptomatology ( 10 ). This implies that early passage to the central nervous system is generally clinically silent and yields chronic, possibly life-long, latent infection ( 11 , 12 ). In Europe and North America, three clonal lineages of T. gondii prevail (type I, II, III), with type II strains being commonly carried by humans and by animals used for meat consumption ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

“…Parasitised dendritic cells (DCs) and other mononuclear phagocytes mediate systemic dissemination of T. gondii ( 15 , 16 ). Passage of T. gondii to the brain parenchyma is restricted by the BBB ( 17 ) and alternative translocation pathways, including trafficking inside leukocytes, have been proposed ( 12 , 18 ). Secretory rhoptry organelles are discharged upon host cell invasion and once the parasite resides in its intracellular niche, the parasitophorous vacuole (PV), dense granules contents are discharged.…”

Section: Introductionmentioning

confidence: 99%

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Toxoplasma effector-induced ICAM-1 expression by infected dendritic cells potentiates transmigration across polarised endothelium

2022

Self Cite

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The obligate intracellular parasite Toxoplasma gondii makes use of infected leukocytes for systemic dissemination. Yet, how infection impacts the processes of leukocyte diapedesis has remained unresolved. Here, we addressed the effects of T. gondii infection on the trans-endothelial migration (TEM) of dendritic cells (DCs) across polarised brain endothelial monolayers. We report that upregulated expression of leukocyte ICAM-1 is a feature of the enhanced TEM of parasitised DCs. The secreted parasite effector GRA15 induced an elevated expression of ICAM-1 in infected DCs that was associated with enhanced cell adhesion and TEM. Consequently, gene silencing of Icam-1 in primary DCs or deletion of parasite GRA15 reduced TEM. Further, the parasite effector TgWIP, which impacts the regulation of host actin dynamics, facilitated TEM across polarised endothelium. The data highlight that the concerted action of the secreted effectors GRA15 and TgWIP modulate the leukocyte-endothelial interactions of TEM in a parasite genotype-related fashion to promote dissemination. In addition to the canonical roles of endothelial ICAM-1, this study identifies a previously unappreciated role for leukocyte ICAM-1 in infection-related TEM.

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The Toxoplasma Effector GRA4 Hijacks Host TBK1 to Oppositely Regulate Anti‐T. Gondii Immunity and Tumor Immunotherapy

Hu,

Zhang,

Xie

et al. 2024

Advanced Science

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Toxoplasma gondii (T. gondii)‐associated polymorphic effector proteins are crucial in parasite development and regulating host anti‐T. gondii immune responses. However, the mechanism remains obscure. Here, it is shown that Toxoplasma effector dense granules 4 (GRA4) restricts host IFN‐I activation. Infection with Δgra4 mutant T. gondii strain induces stronger IFN‐I responses and poses a severe threat to host health. Mechanistically, GRA4 binds to phosphorylated TBK1 to promote TRIM27‐catalyzed K48‐ubiquitination at Lys251/Lys372 residues, which enhances its recognition by autophagy receptor p62, ultimately leading to TBK1 autophagic degradation. Furthermore, an avirulent Δgra4 strain (ME49Δompdc/gra4) is constructed for tumor immunotherapy due to its ability to enhance IFN‐I production. Earlier vaccination with ME49Δompdc/gra4 confers complete host resistance to the tumor compared with the classical ME49Δompdc treatment. Notably, ME49Δompdc/gra4 vaccination induces a specific CD64+MAR‐1+CD11b+ dendritic cell subset, thereby enhancing T cell anti‐tumor responses. Overall, these findings identify the negative role of T. gondii GRA4 in modulating host IFN‐I signaling and suggest that GRA4 can be a potential target for the development of T. gondii vaccines and tumor immunotherapy.

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Early passage of Toxoplasma gondii across the blood–brain barrier

Cited by 22 publications

References 99 publications

Wheat Germ Oil and Propolis Decrease Parasite Burden and Restore Marked Histopathological Changes in Liver and Lung in Mice with Chronic Toxoplasmosis

Wheat Germ Oil and Propolis Decrease Parasite Burden and Restore Marked Histopathological Changes in Liver and Lung in Mice with Chronic Toxoplasmosis

Toxoplasma effector-induced ICAM-1 expression by infected dendritic cells potentiates transmigration across polarised endothelium

The Toxoplasma Effector GRA4 Hijacks Host TBK1 to Oppositely Regulate Anti‐T. Gondii Immunity and Tumor Immunotherapy

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