Temporal transcriptional dynamics in cutaneous leishmaniasis reveal novel targets for therapeutic interventions in a...

Cutaneous leishmaniasis (CL) caused by Leishmania braziliensis results in chronic skin ulceration and remains challenging to treat. While human transcriptomic studies have identified pathways driving immunopathology, the early events of infection and the molecular transitions from lesion formation to healing are still poorly understood. Here, we performed a longitudinal transcriptomic analysis of skin lesions and draining lymph nodes (dLNs) in the BALB/c ear dermal model infected with L. braziliensis, which recapitulates features of human CL. Using bulk RNA sequencing at 2, 6, and 48 hours and at 14, 35, and 77 days post-infection, we characterized differential gene expression, pathway enrichment, and gene co-expression networks. Ulcerated mouse lesions (Day 35) recapitulated 77% of the inflammatory pathways described in human CL, with many persisting at Day 77 despite "clinical healing". Mice displayed additional upregulation of genes linked to macrophage polarization (Il12a, Il12b, Il4), nitric oxide metabolism (Arg1, Nos2) and epidermal differentiation (e.g., Crnn, Rptn, Tchh, Lce members). Gene co-expression analysis revealed stage-specific gene modules (M) associated with early innate responses (M3), tissue damage (M1), epithelial-mesenchymal transition (M4), and skin barrier remodeling (M6). A long non-coding RNA-enriched module (M2) was selectively downregulated during the ulceration. Cross-species comparison of ulcerated lesions revealed 16 conserved microRNAs and 12 shared epigenetic regulators, including Mir155, Mir142, Sp140, and Kdm6b, with known roles in inflammation and tissue repair, representing promising host-directed therapeutic targets. Together, this study provides a comprehensive temporal framework of host responses to L. braziliensis and identifies actionable non-coding RNAs and epigenetic pathways with translational potential for CL therapy.