Identification of Anti-Trypanosoma cruzi Lead Compounds with Putative Immunomodulatory Activity [PublishAheadOfPrint]

In substitution for the current Chagas disease treatment with several relevant side effects, new therapeutic candidates have been extensively investigated. In this context, the balanced interaction between mediators of the host immune response seems to be a key element for therapeutic success, where a pro-inflammatory microenvironment modulated by IL-10 is shown to be relevant to potentiate anti-Trypanosoma cruzi drug activity. This study aimed to identify the potential immunomodulatory activity of the anti-T. cruzi K777, Pyronaridine (PYR) and Furazolidone (FUR) compounds in peripheral blood mononuclear cells (PBMC) from noninfected subjects (NI) and chronic Chagas disease patients (CD). Our results showed low cytotoxicity to PBMC populations, with CC₅₀ = 13.1μM (K777); 9.0μM (PYR) and greater than 20μM (FUR). In addition, K777 showed no impact on the exposure index (EI) of phytohemagglutinin-stimulated leukocytes (PHA), while PYR and FUR treatments induced increased EI of monocytes and T lymphocytes at late stages of apoptosis in NI subjects. Moreover, K777 induced a more prominent pro-inflammatory response (TNF-α⁺CD8⁺/CD4⁺, IFN-⁺CD4⁺/CD8⁺ modulated by IL-10 (IL-10⁺CD4⁺T/CD8⁺T) in comparison with PYR (TNF-α⁺CD8⁺, IL-10⁺CD8⁺) and FUR (TNF-α⁺CD8⁺, IL-10⁺CD8⁺). Signature analysis of intracytoplasmic cytokines corroborated with the proinflammatory/modulated (K777) and pro-inflammatory (PYR and FUR) profiles previously found. In conclusion, K777 lead compound may induce beneficial changes in the immunological profile of patients presenting the chronic phase of Chagas disease and may contribute to a more effective therapy against the disease.

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