From dogma to data:charting a path forward for clinico-immunological research in Ethiopian cutaneous leishmaniasis

Background: Rooted in long-standing assumptions and adapted from classifications mainly used for Latin American cutaneous leishmaniasis (CL), the nationally recommended clinical categories in Ethiopia for CL remain limited to localized cutaneous leishmaniasis (LCL), mucocutaneous leishmaniasis (MCL), and diffuse cutaneous leishmaniasis (DCL). However, these categories are associated with immune mechanisms which have not been validated in the Ethiopian context and thus risk misrepresenting the true clinical and immunopathological diversity. In this opinion piece, we will therefore outline key knowledge gaps and challenges in current clinico-immunological research on Ethiopian CL. Main body: In Ethiopia, Leishmania aethiopica is often assumed as the causative agent of these ‘LCL’, ‘MCL’ and ‘DCL’ forms, yet significant gaps in knowledge urge caution. For example, adoption of this ‘LCL’, ‘MCL’ and ‘DCL’ terminology and the associated immune mechanisms has led to inconsistent results. Most immunological studies on Ethiopian CL have focused on peripheral blood, resulting in little information about immune processes in the lesion, the original site of infection. Adding to the complexity, other species (including L. major, L. donovani and L. tropica as well as L. aethiopica hybrids) also circulate, with reports of Leishmania RNA virus co-infection. To address these challenges, we propose a multidimensional approach that combines standardized clinical documentation with appropriate lesion and blood sampling for in-depth profiling of both immune responses and parasite diversity. Adopting this holistic approach will require inclusive (inter)national collaborations with a focus on promoting equitable biobank and data sharing which will strengthen local research capacities. Conclusions: By addressing the main challenges and knowledge gaps in current clinico-immunological research through a multidimensional approach, this opinion aims to provide the tools to achieve a better and unbiased understanding of the immunopathogenesis of Ethiopian CL, a severe yet under-investigated disease. Such progress is essential for improving CL management in Ethiopia and aligns with the World Health Organization priority on controlling CL.