Beyond the parasite: skin-intrinsic cytolytic circuits drive disease in cutaneous leishmaniasis and reveal targets for host-directed therapy.

Abstract

SUMMARYCutaneous leishmaniasis (CL) is a globally prevalent parasitic disease in which tissue pathology often arises primarily from immune-mediated damage rather than uncontrolled parasite replication. Despite effective Th1 responses and the production of IFN-γ, lesions often fail to resolve, highlighting an uncoupling of protective immunity from disease pathogenesis. This review synthesizes evidence from experimental models and human studies demonstrating that skin-intrinsic cytolytic inflammatory circuits-rather than parasite burden-are dominant drivers of lesion persistence and treatment failure in CL. Central to this pathway is the accumulation of cytotoxic CD8⁺ T cells within lesions, where perforin-dependent cell death triggers NLRP3 inflammasome activation and IL-1β production. IL-1β acts as a potent amplifier of inflammation by promoting neutrophil recruitment, tissue injury, and local hypoxia, which further programs pathogenic CD8⁺ T-cell differentiation. These responses are exacerbated by alterations of the skin microbiome, particularly the dominance of Staphylococcus aureus, and are normally constrained by Foxp3⁺ regulatory T cells that limit excessive IFN-γ-driven cytotoxicity. In parallel, parasite persistence within permissive macrophage subsets provides a continuous antigenic stimulus that sustains inflammation without achieving sterilizing immunity. Together, these interconnected pathways form a self-reinforcing inflammatory circuit that promotes ulceration, chronic disease, and therapeutic failure. Importantly, this pathogenic network is largely dispensable for parasite control and, therefore, provides multiple targets for host-directed therapies that could complement anti-parasitic drugs and improve clinical outcomes in CL.