Transcriptomic and macrophage polarization signatures define anergic diffuse and mucosal forms of severe American...

American cutaneous leishmaniasis (ACL) comprises a complex spectrum of immunopathological conditions in which Leishmania (V.) braziliensis and L. (L.) amazonensis elicit markedly divergent host responses. Mucosal leishmaniasis (ML) is characterized by a hyperergic, pro-inflammatory state, whereas anergic diffuse cutaneous leishmaniasis (ADCL) involves a profound impairment of cell-mediated immunity, respectively. The molecular sensors and metabolic circuits that dictate this immunological divergence remain poorly understood. We hypothesized that parasite species-specific programs orchestrate distinct macrophage polarization states, leading either tissue destruction or parasite persistence. We performed transcriptomic profiling (RNA-seq) of skin and mucosal biopsies from 20 ACL patients representing the full clinical spectrum (ADCL, ML, and localized forms) and from healthy controls. Computational deconvolution and gene regulatory network analyses were integrated with immunohistochemical validation of macrophage state markers. Unsupervised clustering identified parasite species as the principal determinant of lesion transcriptomes. ADCL lesions displayed a distinct MARCO-high immunometabolic program associated with upregulation of PPARG, SCARB1, and LRP1, consistent with enhanced fatty acid uptake and oxidative phosphorylation. The immunopathological analyses demonstrated that this signature was associated with a regulatory/anti-inflammatory (M2-like) macrophage phenotype (CD163⁺/IL-10⁺) in ADCL, whereas ML was characterized by an inflammatory (M1-like) macrophage phenotype (CD68⁺/iNOS⁺/TNF-α⁺/IFN-γ⁺). These findings indicate that MARCO expression and macrophage polarization vary markedly across clinical forms of ACL and are strongly influenced by Leishmania species. This interaction promotes immunometabolic reprogramming that supports L. (L.) amazonensis persistence in ADCL, or proinflammatory responses associated with tissue damage in ML due to L. (V.) braziliensis. These processes highlight potential targets for immunotherapeutic strategies aimed at restoring host immunity in severe ACL.