Oral Treatment With Heat Shock Protein 65‐Producing Lactococcus lactis Induces Regulatory T Cells, Modulating Inflammatory Response in Leishmania braziliensis Infection

Cutaneous leishmaniasis (CL), a neglected tropical disease prevalent in Brazil, is caused by Leishmania braziliensis ( L. braziliensis ) and is marked by ulcerative skin lesions and an exacerbated Th1‐driven inflammatory response. This study investigates the therapeutic potential of oral tolerance (OT) induced by a genetically modified strain of Lactococcus lactis ( L. lactis ) producing heat shock protein 65 (HSP65) from Mycobacterium leprae in a murine model of CL. BALB/c mice were infected with L. braziliensis and treated orally with HSP65‐producing L. lactis or control L. lactis (empty vector) for four consecutive days, starting at 4 weeks post‐infection. Mice receiving HSP65‐producing L. lactis showed reduced lesion size and parasite burden. Cytokine analysis in draining lymph nodes revealed a shift from a pro‐inflammatory IFN‐γ response to an increased IL‐10 production, correlating with milder inflammation and less tissue damage. Additionally, the treatment promoted an increase in regulatory T cells (Tregs), including CD4 + CD25 + FOXP3 + and CD4 + LAP + (membrane‐associated TGF‐β) cells in the draining lymph nodes. This therapeutic effect was not observed in a more severe model of CL using Leishmania major. This study underscores the potential of oral tolerance induction using HSP65‐producing L. lactis as a promising immunoregulatory therapeutic approach for some chronic inflammatory infections, mainly those that display a primed balance in immune response.