Abstract
<jats:p>Leishmaniasis is a widely distributed vector-borne neglected tropical disease for which current therapeutic options remain suboptimal because of toxicity, emerging drug resistance, and limited induction of long-term protective immunity. Immunotherapeutic approaches that enhance host protective immune responses therefore represent an attractive alternative strategy. In this study, we evaluated the immunotherapeutic efficacy of recombinant Leishmania (L.) infantum eukaryotic initiation factor (LieIF) in BALB/c murine models of cutaneous (Leishmania (L.) major) and visceral (Leishmania (L.) infantum) leishmaniasis. Mice received recombinant LieIF after infection, and disease progression, parasite burden, humoral and cellular immune responses and immune-related gene expression were assessed. LieIF treatment significantly attenuated lesion progression in cutaneous leishmaniasis and reduced parasite burden in visceral disease model. Therapeutic efficacy was associated with enhanced Th1-associated immune responses, including increased frequencies of IFN-γ-producing CD4⁺ lymphocytes, increased IL-12-producing cells, and elevated expression of the Th1-associated genes (transcription factor Tbx21 and IFN-γ). In the cutaneous model, treatment also reduced Leishmania-specific IgG1 responses, whereas antibody isotype responses were largely unchanged in visceral leishmaniasis, indicating that protection was primarily associated with cellular rather than humoral immune modulation. The demonstration of therapeutic efficacy in two distinct experimental models highlights the broad immunomodulatory capacity of LieIF. Collectively, these findings identify LieIF as a promising host-directed immunotherapeutic candidate for leishmaniasis and provide a strong rationale for further studies to optimize treatment regimens, elucidate its mechanisms of action, and evaluate its efficacy in combination with conventional antileishmanial chemotherapy.</jats:p>