Imiquimod Reverses Chronic Toxoplasmosis-Associated Behavioral and Neurocognitive Anomalies in a Rat Model.

Toxoplasma gondii is the etiologic agent of toxoplasmosis, a highly prevalent parasitosis. Toxoplasma gondii (T. gondii) transits in the brain from acute (AT) to chronic toxoplasmosis (CT), under host immune control. In immunocompromised patients, reactivation of CT is potentially life-threatening. Behavioral and neurological complications have been associated with CT. Furthermore, an effective treatment targeting CT is still lacking. We previously reported the efficacy of imiquimod against CT. Here, we demonstrate the molecular effects of imiquimod or imiquimod followed by the clinically used combination of sulfadiazine and pyrimethamine (SDZ + PYR) on CT-associated behavior in a rat model. Imiquimod decreased the number of cysts in the brains of chronically infected rats due to an induced reactivation of bradyzoites into tachyzoites. Importantly, this decrease was more pronounced in rats treated with imiquimod followed by SDZ + PYR. Rats chronically infected with T. gondii exhibited an anxiety-like behavior. Notably, treatment with imiquimod reversed this behavior aberrancy, with even a more pronounced effect with imiquimod followed by SDZ/PYR. Similarly, rats chronically infected with T. gondii exhibited learning deficits, and imiquimod alone or followed by SDZ/PYR reversed this behavior. Our results enhance our knowledge of the implications of CT on behavioral aberrancies and highlight the potency of imiquimod followed by SDZ + PYR on these CT-associated complications.

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.

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.