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Metabolite profiling of experimental cutaneous leishmaniasis lesions demonstrates significant perturbations in tissue phospholipids

Adwaita R. Parab, Diane Thomas, Sharon Lostracco-Johnson, Jair Lage de Siqueira-Neto, James McKerrow, Pieter C. Dorrestein, Laura-Isobel McCall
doi: https://doi.org/10.1101/2020.05.13.094649
Adwaita R. Parab
1Department of Microbiology and Plant Biology, University of Oklahoma, Norman, Oklahoma, United States of America
2Laboratories of Molecular Anthropology and Microbiome Research, University of Oklahoma, Norman, Oklahoma, United States of America
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Diane Thomas
3Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America
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Sharon Lostracco-Johnson
3Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America
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Jair Lage de Siqueira-Neto
3Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America
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James McKerrow
3Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America
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Pieter C. Dorrestein
3Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America
4Center for Microbiome Innovation, University of California San Diego, La Jolla, California, United States of America
5Collaborative Mass Spectrometry Innovation Center, University of California San Diego, La Jolla, California, United States of America
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Laura-Isobel McCall
1Department of Microbiology and Plant Biology, University of Oklahoma, Norman, Oklahoma, United States of America
2Laboratories of Molecular Anthropology and Microbiome Research, University of Oklahoma, Norman, Oklahoma, United States of America
6Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, United States of America
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  • For correspondence: lmccall@ou.edu
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Abstract

Each year 700,000 to 1.2 million new cases of cutaneous leishmaniasis (CL) are reported and yet CL remains one of thirteen diseases classified as neglected tropical diseases (NTDs). Leishmania major is one of several different species of that same 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 lead to new drug targets. In this study, samples were collected from mice infected in the ear and 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 select phosphocholines (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 the host metabolism and may lead to new curative measures against infection with Leishmania.

Author summary Cutaneous leishmaniasis (CL) is one of thirteen neglected tropical diseases in the world today. It is an infectious disease with a wide distribution spanning five continents, with increasing distribution expected due to climate change. CL manifests as skin lesions and ulcers that are disabling and stigmatized. With the current treatment options being limited, studying host-pathogen metabolism can uncover mechanisms of disease pathogenesis that may lead to new curative measures against infection. In this paper we used untargeted metabolomics to address molecular-level changes occurring in vivo in experimental skin lesions of Leishmania major. Distinct global metabolic profiles were observed. Total phosphocholines (PCs) and those in the lower m/z ranges were significantly higher at the site of the skin lesion in the ear. In addition, specific PCs as well as PCs of varied m/z ranges were also affected at healthy-appearing lesion-adjacent sites, indicating that infection-induced metabolic perturbations are not restricted to the lesion site. Ultimately, these results provide essential clues to the metabolic pathways affected by CL.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 15, 2020.
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Metabolite profiling of experimental cutaneous leishmaniasis lesions demonstrates significant perturbations in tissue phospholipids
Adwaita R. Parab, Diane Thomas, Sharon Lostracco-Johnson, Jair Lage de Siqueira-Neto, James McKerrow, Pieter C. Dorrestein, Laura-Isobel McCall
bioRxiv 2020.05.13.094649; doi: https://doi.org/10.1101/2020.05.13.094649
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Metabolite profiling of experimental cutaneous leishmaniasis lesions demonstrates significant perturbations in tissue phospholipids
Adwaita R. Parab, Diane Thomas, Sharon Lostracco-Johnson, Jair Lage de Siqueira-Neto, James McKerrow, Pieter C. Dorrestein, Laura-Isobel McCall
bioRxiv 2020.05.13.094649; doi: https://doi.org/10.1101/2020.05.13.094649

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