Imiquimod Targets Toxoplasmosis Through Modulating Host Toll-Like Receptor-MyD88 Signaling

Abstract

Toxoplasma gondii is a prevalent parasite of medical and veterinary importance. Tachyzoïtes and bradyzoïtes are responsible for acute and chronic toxoplasmosis (AT and CT), respectively. In immunocompetent hosts, AT evolves into a persistent CT, which can reactivate in immunocompromised patients with dire consequences. Imiquimod is an efficient immunomodulatory drug against certain viral and parasitic infections. In vivo, treatment with Imiquimod, throughout AT, reduces the number of brain cysts while rendering the remaining cysts un-infectious. Post-establishment of CT, Imiquimod significantly reduces the number of brain cysts, leading to a delay or abortion of reactivation. At the molecular level, Imiquimod upregulates the expression of Toll-like receptors 7, 11, and 12, following interconversion from bradyzoïtes to tachyzoïtes. Consequently, MyD88 pathway is activated, resulting in the induction of the immune response to control reactivated Toxoplasma foci. This study positions Imiquimod as a potent drug against toxoplasmosis and elucidates its mechanism of action particularly against chronic toxoplasmosis, which is the most prevalent form of the disease.

Bicyclic azetidines target acute and chronic stages of Toxoplasma gondii by inhibiting parasite phenylalanyl t-RNA synthetase

“…Notably, neither of these compounds is able to completely eradicate chronic infection, similar to other recently described compounds that show efficacy in the mouse model of toxoplasmosis 42 . Other recent studies show that modulation of immune responses using the TLR7 agonist imiquimod can reduce chronic infection and suppress subsequent infection by treated bradyzoites in an immunocompetent mouse model 43 . Using a more stringent model for reactivation of chronic infection, it was shown that ATP mimetics that specifically inhibit calcium-dependent protein kinase 1 (CPKD1) both reduce the burden of chronic infection 44 and prevent reactivation in an immunocompromised mouse model of toxoplasmosis 27 , 45 .…”

Impact of Plant-Based Foods and Nutraceuticals on Toxoplasma gondii Cysts: Nutritional Therapy as a Viable Approach for Managing Chronic Brain Toxoplasmosis

“…At least 50 promising anti-cyst candidates have been identified through screening of compound libraries, target-based drug design, or repurposing of Food and Drug Administration (FDA)approved drugs [see review (78)]. For example, imiquimod has recently been identified as a promising prophylactic and therapeutic drug against brain cyst burden and cyst reactivation through its immunomodulatory role (79). While the discovery of pharmacological cysticidal agents is underway, nutritional therapy has emerged as a new approach to cope with chronic T. gondii infection.…”

“…To improve the predictive translatability of animal models, the nutritional products must be tested in a large sample and in different infection models. Studies involving immunodeficient animal models (e.g., dexamethasone-induced immunosuppression) could also help in determining whether nutrition mitigates the recrudescence of latent CNS infection (79).…”

Comprehensive Overview of Toxoplasma gondii-Induced and Associated Diseases

“…Importantly, treatment with imiquimod, postestablishment of CT, significantly reduces the number of brain cysts, leading to a delay or abortion of reactivation. Molecularly, imiquimod upregulated the expression of Toll-like receptors and activated the MyD88 pathway, resulting in the induction of the immune response to control reactivation [170].…”