Host immunopathology in Zoonotic Cutaneous Leishmaniasis: Exploring the impact of the diversity of Leishmania major strains from two Moroccan foci.

Cutaneous leishmaniasis (CL) is characterized by polymorphic dermal lesions and remains a major public health concern worldwide. This study assessed the impact of different Moroccan Leishmania major strains on host immunopathology. Swiss mice were infected with five L. major strains from Tinghir and Zagora Moroccan endemic foci and sacrificed at 3 and 13 weeks post-infection (p.i). Mice exhibited distinct infection profiles, with lesions appearing between the 2nd and 3rd weeks p.i and stabilizing between the 8th and 12th weeks pi. Two-way ANOVA showed a significant association between lesion size and strain region (p < 0.01), with Zagora strains exhibiting the largest lesions. RT-qPCR analysis revealed that Zagora strains downregulated IL-1β in draining lymph nodes (DLNs) and footpads at 3 and 13 weeks p.i respectively; they also downregulated iNOS in footpads and DLNs at 13 weeks p.i. Unsupervised principal component analysis, integrating lesion size, IL-1β, and iNOS expression with strain region, organ, and infection time, revealed significant associations among these parameters. By integrating these significant parameters, we built a multivariable model with IL-1β quantification as the outcome. This model revealed a positive association of IL-1β with iNOS (p < 0.001), as well as with the spleen (p < 0.001) and footpad (p < 0.01). Conversely, it showed a negative association of IL-1β with the Zagora strains (p < 0.05) and with infection time (13 weeks pi; p < 0.05). Transcriptome analysis highlighted early IL-1β induction in L. major infection, associated with an inflammatory response. Thus, IL-1β and iNOS modulation by L. major strains may explain the clinical polymorphism of CL patients' lesions.