Toxoplasmosis: Current and Emerging Parasite Druggable Targets

Toxoplasmosis is a prevalent disease affecting a wide range of hosts including approximately one-third of the human population. It is caused by the sporozoan parasite Toxoplasma gondii (T. gondii), which instigates a range of symptoms, manifesting as acute and chronic forms and varying from ocular to deleterious congenital or neuro-toxoplasmosis. Toxoplasmosis may cause serious health problems in fetuses, newborns, and immunocompromised patients. Recently, associations between toxoplasmosis and various neuropathies and different types of cancer were documented. In the veterinary sector, toxoplasmosis results in recurring abortions, leading to significant economic losses. Treatment of toxoplasmosis remains intricate and encompasses general antiparasitic and antibacterial drugs. The efficacy of these drugs is hindered by intolerance, side effects, and emergence of parasite resistance. Furthermore, all currently used drugs in the clinic target acute toxoplasmosis, with no or little effect on the chronic form. In this review, we will provide a comprehensive overview on the currently used and emergent drugs and their respective parasitic targets to combat toxoplasmosis. We will also abridge the repurposing of certain drugs, their targets, and highlight future druggable targets to enhance the therapeutic efficacy against toxoplasmosis, hence lessening its burden and potentially alleviating the complications of its associated diseases.

Identification of Oocyst-Driven Toxoplasma gondii Infections in Humans and Animals through Stage-Specific Serology—Current Status and Future Perspectives

The apicomplexan zoonotic parasite Toxoplasma gondii has three infective stages: sporozoites in sporulated oocysts, which are shed in unsporulated form into the environment by infected felids; tissue cysts containing bradyzoites, and fast replicating tachyzoites that are responsible for acute toxoplasmosis. The contribution of oocysts to infections in both humans and animals is understudied despite being highly relevant. Only a few diagnostic antigens have been described to be capable of discriminating which parasite stage has caused an infection. Here we provide an extensive overview of the antigens and serological assays used to detect oocyst-driven infections in humans and animals according to the literature. In addition, we critically discuss the possibility to exploit the increasing knowledge of the T. gondii genome and the various ‘omics datasets available, by applying predictive algorithms, for the identification of new oocyst-specific proteins for diagnostic purposes. Finally, we propose a workflow for how such antigens and assays based on them should be evaluated to ensure reproducible and robust results.

Comprehensive Overview of Toxoplasma gondii-Induced and Associated Diseases

Toxoplasma gondii (T. gondii) is a prevalent protozoan parasite of medical and veterinary significance. It is the etiologic agent of toxoplasmosis, a neglected disease in which incidence and symptoms differ between patients and regions. In immunocompetent patients, toxoplasmosis manifests as acute and chronic forms. Acute toxoplasmosis presents as mild or asymptomatic disease that evolves, under the host immune response, into a persistent chronic disease in healthy individuals. Chronic toxoplasmosis establishes as latent tissue cysts in the brain and skeletal muscles. In immunocompromised patients, chronic toxoplasmosis may reactivate, leading to a potentially life-threatening condition. Recently, the association between toxoplasmosis and various diseases has been shown. These span primary neuropathies, behavioral and psychiatric disorders, and different types of cancer. Currently, a direct pre-clinical or clinical molecular connotation between toxoplasmosis and most of its associated diseases remains poorly understood. In this review, we provide a comprehensive overview on Toxoplasma-induced and associated diseases with a focus on available knowledge of the molecular players dictating these associations. We will also abridge the existing therapeutic options of toxoplasmosis and highlight the current gaps to explore the implications of toxoplasmosis on its associated diseases to advance treatment modalities.

Evaluation of the Reproductive Ability of Male Rats in Acute Toxoplasmosis

Toxoplasmosis is a parasitic disease of humans and animals caused by Toxoplasma gondii. Toxoplasma is an intracellular parasite that belongs to the simplest and has a complex development cycle. Infection with Toxoplasma is possible orally, transplacentally, percutaneously (if the integrity of the skin is damaged). This invasion is often the cause of problems with bearing pregnancy, as well as the development of congenital anomalies in children. The purpose of the study was to study the reproductive ability of male rats in acute toxoplasmosis. Materials and methods. The experiment was performed on 90 female and 45 male Wistar rats with a body weight of 180-200 g. The intact control males were orally injected with 2 ml of 0.2% starch gel. Experimental groups of males were infected with an invasive Toxoplasma gondii culture at a dose of 25 tachyzoites per 1 g of body weight (5000 tachyzoites per rat) and 50 tachyzoites per 1 g of body weight (10000 tachyzoites per rat). Then the males of all groups were coupled with the females for 3 days. The effect of toxoplasmas on the reproductive ability of male rats was assessed by the development of pregnancy and changes in the levels of pre- and post-implantation embryo death in female rats on the 7th, 14th, and 21st days after pregnancy. To account for changes in the pre- and post-implantation death of embryos in female rats after removal from the experiment, the uterus and ovaries were isolated, the uterine horns were opened, the number of implantation sites, the total number of embryos, the number of living and dead embryos, the number of resorption, and the number of yellow bodies in the ovaries were determined. Results and discussion. In the females of the 4th, 5th and 6th groups (coupling with males infected at the dose of 25 tachyzoites per 1 g of body weight), a decrease in the number of implantation sites in the uterus, the total number of embryos and the number of live embryos was recorded by 1.8-1.9 times compared to the control parameters. In female rats of the 7th, 8th and 9th groups (coupling with males infected at the dose of 50 tachyzoites per 1 g of body weight), there was a decrease in the number of implantation sites in the uterus, the total number of embryos and the number of live embryos by 5.6-6.8 times compared to the control. When compared to the results obtained from the females of the 4th, 5th and 6th groups, a decrease in these indicators was recorded by 3.1-3.5 times. Conclusion. Toxoplasma gondii has an effect on reproductive capacity in male rats expressed in changes of the levels of preimplantation mortality in female rats. The obtained effect depends on the dose of infection and the period of parasitosis development in males

With Chitosan and PLGA as the Delivery Vehicle, Toxoplasma gondii Oxidoreductase-Based DNA Vaccines Decrease Parasite Burdens in Mice

Toxoplasma gondii (T. gondii) is an intracellular parasitic protozoan that can cause serious public health problems. However, there is no effectively preventive or therapeutic strategy available for human and animals. In the present study, we developed a DNA vaccine encoding T. gondii oxidoreductase from short-chain dehydrogenase/reductase family (TgSDRO-pVAX1) and then entrapped in chitosan and poly lactic-co-glycolic acid (PLGA) to improve the efficacy. When encapsulated in chitosan (TgSDRO-pVAX1/CS nanospheres) and PLGA (TgSDRO-pVAX1/PLGA nanospheres), adequate plasmids were loaded and released stably. Before animal immunizations, the DNA vaccine was transfected into HEK 293-T cells and examined by western blotting and laser confocal microscopy. Th1/Th2 cellular and humoral immunity was induced in immunized mice, accompanied by modulated secretion of antibodies and cytokines, promoted the maturation and MHC expression of dendritic cells, and enhanced the percentages of CD4+ and CD8+ T lymphocytes. Immunization with TgSDRO-pVAX1/CS and TgSDRO-pVAX1/PLGA nanospheres conferred significant immunity with lower parasite burden in the mice model of acute toxoplasmosis. Furthermore, our results also lent credit to the idea that TgSDRO-pVAX1/CS and TgSDRO-pVAX1/PLGA nanospheres are substitutes for each other. In general, the current study proposed that TgSDRO-pVAX1 with chitosan or PLGA as the delivery vehicle is a promising vaccine candidate against acute toxoplasmosis.