Proteome profiling of cutaneous leishmaniasis lesions due to dermotropic Leishmania donovani in Sri Lanka

Characterization of the host response in cutaneous leishmaniasis (CL) through proteome profiling has gained limited insights in leishmaniasis research, in comparison to that of the parasite. The primary objective of this study was to comprehensively analyze the proteomic profile of the skin lesions tissues in patients with CL, by mass spectrometry, and subsequent validation of these findings through immunohistochemical methods. Sixty-seven proteins exhibited significant differential expression between tissues of CL lesions and healthy controls (p<0.01), representing numerous enriched biological processes within the lesion tissue, as evident by both the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. Among these, the integrated endoplasmic reticulum stress response (IERSR) emerges as a pathway characterized by the up-regulated proteins in CL tissues compared to healthy skin. Expression of endoplasmic reticulum (ER) stress sensors, inositol-requiring enzyme-1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6) in lesion tissue was validated by immunohistochemistry. In conclusion, proteomic profiling of skin lesions carried out as a discovery phase study revealed a multitude of probable immunological and pathological mechanisms operating in patients with CL in Sri Lanka, which needs to be further elaborated using more in-depth and targeted investigations. Author SummaryCutaneous leishmaniasis (CL), is a skin infection caused by a type of single-celled parasite. These parasites are usually transmitted through the bite of infected sandflies. In Sri Lanka, CL is caused by a parasite type that usually causes a more severe disease form, known as visceral leishmaniasis. Interaction between the parasite and the human host is important in determining the disease outcome and hence, we conducted a study to look at the proteins in the skin lesions of people with CL using a technique called mass spectrometry. We found 67 proteins that were different between CL lesions and healthy skin. These proteins are involved in various processes in the body, and one specific process called the integrated endoplasmic reticulum stress response (IERSR) was more active in CL patients. We confirmed this by studying specific proteins related to stress in the lesion tissue. In conclusion, our study uncovered several potential immune and disease-related mechanisms in CL patients in Sri Lanka. However, more detailed investigations are needed to fully understand these processes.