IMMUNE REGULATION AND VACCINE DEVELOPMENT IN LEISHMANIASIS

National Institute Of Allergy And Infectious Diseases

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Abstract

In murine models of visceral leishmaniasis (VL), the parasitization of resident Kupffer cells (resKCs) drives early Leishmania infantum growth in the liver, leading to granuloma formation and subsequent parasite control. Using the chronic VL model, we demonstrate that polyclonal resKCs redistributed to form granulomas outside the sinusoids, creating an open sinusoidal niche that was gradually repopulated by monocyte-derived KCs (moKCs) acquiring a tissue specific, homeostatic profile. Early-stage granulomas predominantly consisted of CLEC4F+KCs. In contrast, late-stage granulomas led to remodeling of the sinusoidal network and contained monocyte-derived macrophages (momacs) along with KCs that downregulated CLEC4F, with both populations expressing iNOS and pro-inflammatory chemokines. During late-stage infection, parasites were largely confined to CLEC4F-KCs. Reduced monocyte recruitment and increased resKCs proliferation in infected Ccr2-/- mice impaired parasite control. These findings show that the ontogenic heterogeneity of granuloma macrophages is closely linked to granuloma maturation and the development of hepatic immunity in VL. Persistent infections by Leishmania following clinical cure are poorly understood, despite their relevance to disease reactivation and cyclical transmission. We identified CD206+ dermal tissue-resident macrophages (TRMs) as the principal host cells harboring L. major in healed lesions of resistant C57BL/6 mice. We showed that despite the strong Th1 environment of the infected skin, these embryonically derived, M2-like macrophages are sustained by a localized type 2 immune circuitry involving CCL24 and TSLP from TRMs, IL-5 from ILC2s, and IL-4 and 13 from eosinophils. Genetic or therapeutic disruption of any component of this circuit via TRM depletion, IL-5 neutralization, or conditional cytokine ablation reduced parasite burdens and achieved sterile cure in some mice. The carbohydrate-rich molecules on the surface of Leishmania are crucial for the parasite’s infectivity in both the host and vector. Among these, galactose moieties have been identified as promising targets for vaccine development against leishmaniasis. We investigated the potential of human monoclonal antibodies (mAbs) targeting alpha-Gal to prevent L. major infection. Our results demonstrate that alpha-Gal-specific mAbs effectively bind to and agglutinate both metacyclic and procyclic L. major promastigotes. To assess the protective efficacy of these mAbs, we challenged alpha 1,3-galactosyltransferase-deficient mice with L. major. The mAb AG030 significantly delayed the onset of skin lesions and reduced the parasite burden. These findings provide proof of concept that alpha-Gal-targeting mAbs could serve as therapeutic interventions to prevent cutaneous leishmaniasis.