Dysregulation of Glycerophosphocholines in the Cutaneous Lesion Caused by Leishmania major in Experimental Murine Models.

Adwaita R Parab,Pieter C Dorrestein,Jair L Siqueira-Neto,Sharon Lostracco-Johnson,Laura-Isobel Mccall,Diane Thomas,James H Mckerrow

doi:10.3390/pathogens10050593

Abstract

Cutaneous leishmaniasis (CL) is the most common disease form caused by a Leishmania parasite infection and considered a neglected tropical disease (NTD), affecting 700,000 to 1.2 million new cases per year in the world. Leishmania major is one of several different species of the Leishmania genus that can cause CL. Current CL treatments are limited by adverse effects and rising resistance. Studying disease metabolism at the site of infection can provide knowledge of new targets for host-targeted drug development. In this study, tissue samples were collected from mice infected in the ear or footpad with L. major and analyzed by untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). Significant differences in overall metabolite profiles were noted in the ear at the site of the lesion. Interestingly, lesion-adjacent, macroscopically healthy sites also showed alterations in specific metabolites, including selected glycerophosphocholines (PCs). Host-derived PCs in the lower m/z range (m/z 200–799) showed an increase with infection in the ear at the lesion site, while those in the higher m/z range (m/z 800–899) were decreased with infection at the lesion site. Overall, our results expanded our understanding of the mechanisms of CL pathogenesis through host metabolism and may lead to new curative measures against infection with Leishmania.

Highlights

Leishmaniasis affects people in 88 countries worldwide in tropical, subtropical and temperate regions, putting approximately 350 million individuals at risk of infection, with approximately 12 million battling the disease [1]
Random forest machine learning analysis [14] was performed to identify the metabolites most affected by infection in both experimental systems, with annotation performed using molecular networking and Global Natural Products Social Molecular Networking platform (GNPS) [15]
Annotatable molecules most highly affected by infection include metabolites of the glycerophosphocholine family of phospholipids, including PC O-38:5 (m/z 794.6051 RT 4.42 min), PC O-36:3 (m/z 770.605 RT 4.58 min), PC

Summary

Introduction

Leishmaniasis affects people in 88 countries worldwide in tropical, subtropical and temperate regions, putting approximately 350 million individuals at risk of infection, with approximately 12 million battling the disease [1]. Promastigotes differentiate into the amastigote stage, which multiply and affect various tissue types depending on whether infection is initiated by a viscerotropic or dermotropic parasite strain [4,5]. This initiates the clinical manifestations of the disease. Humans as well as other mammals serve as host reservoirs for the parasite [6]

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Results