Ursolic Acid Reduces Parasite Burden Through Th-1 Mediated Immunomodulation in Experimental Visceral Leishmaniasis.

Abstract

Objective: Trypanosomatidae covers major pathogens of human host including the deadly Leishmania donovani parasite causing visceral leishmaniasis. This study aims to find the commonly expressed proteins among the different trypanosomatidae parasites having therapeutic efficacies and to elucidate the therapeutic potential of naturally occurring dietary compound Ursolic acid (UA) against the common targets and to understand its immunomodulatory effect in terms of L. donovani infection.

Methods: In- silico methods were applied to identify the non-human, commonly expressed protein with high therapeutic efficacies among the five major pathogen of Trypanosomatidae including L. donovani, L. infantum, L. major, Trypanosoma cruzi, and T. brucei. The affinity between the target proteins and UA was investigated through molecular docking. Immunomodulatory and antileishmanial efficacy of UA was studied using different in vitro and in vivo techniques.

Results: Our study identified 13 commonly expressed proteins with therapeutic efficacies across five different trypanosomatidae parasites. Docking analysis revealed that UA had a substantial binding affinity toward potential therapeutic targets of L. donovani. UA was found to be highly effective in killing promastigotes and amastigotes in infected macrophages in vitro. In L. donovani-infected macrophages, UA efficiently increased NO production, which is accompanied by the elevated expression of pro-inflammatory cytokines (IL-12, TNF-α) and the downregulation of IL-10 and TGF-β. During in vivo study in infected BALB/c mice, UA shows enhanced T-cell proliferation and IL-2 expression in splenocytes with subsequent decrease in hepato-splenic parasite burden.

Conclusions: The widespread occurrence of UA in common fruits and herbs used in daily life contributes to its potential dietary intake and associated health benefits. Our study further highlighted the immunomodulatory role of UA, potentially influencing both the innate and adaptive immune responses. Overall, the study identified the significant drug targets among the family of trypanosomatidae parasites and demonstrated UA's possible effectiveness against L. donovani infection.