Investigation of host metabolic interactions in trypanosomatid infections
File(s)
Author(s)
Lamour, Sabrina Danielle
Type
Thesis
Abstract
Infections with parasitic trypanosomatids cause serious neglected tropical diseases, which include cutaneous leishmaniasis (CL), causing skin ulceration, and human African trypanosomiasis (HAT), which causes flu-like symptoms followed by neurological features and is fatal if left untreated. Current disease management in both cases is inappropriate owing to suboptimal diagnosis and limited drugs with variable efficacy and severe adverse effects. Further research into their pathogeneses is critical for the discovery of novel diagnostic tools and therapeutic targets.
Experimental Leishmania (L.) major infection in two murine CL models with differing pathologies, and HAT caused by Trypanosoma brucei (T. b.) rhodesiense infection, were investigated from a systemic metabolic perspective, using 1H nuclear magnetic resonance (NMR) spectroscopy. This was combined with cytokines and (for CL models) faecal microbial diversity measures, as additional markers of host response.
In addition to the discovery of a range of Leishmania infection-associated markers, including putative parasitic end-products alanine and succinate, significant divergences in measures were observed between the self-healing and non-healing CL mouse models. Such differences included variations in glucose and lipid metabolism, in inflammatory status, and in faecal Clostridia and Gammaproteobacteria abundance. Striking differences were also observed in the degree of statistical links between these measures, using newly developed correlation network analyses, implying that a rapid and inter-connected systems response was required for effective parasitic elimination.
This project also represents the first study to provide a comprehensive description of host metabolic changes in HAT. A total of 16 and 31 significant discriminatory metabolites were determined in plasma via 1H NMR spectroscopy and ultra-performance liquid chromatography/mass spectrometry (UPLC-MS), respectively, including membrane phospholipids and amino acids, linked with inflammation. These findings provide a unique insight into underlying metabolic interactions that may contribute to pathology, and reveal a set of infection-related markers with possible diagnostic potential for CL and HAT.
Experimental Leishmania (L.) major infection in two murine CL models with differing pathologies, and HAT caused by Trypanosoma brucei (T. b.) rhodesiense infection, were investigated from a systemic metabolic perspective, using 1H nuclear magnetic resonance (NMR) spectroscopy. This was combined with cytokines and (for CL models) faecal microbial diversity measures, as additional markers of host response.
In addition to the discovery of a range of Leishmania infection-associated markers, including putative parasitic end-products alanine and succinate, significant divergences in measures were observed between the self-healing and non-healing CL mouse models. Such differences included variations in glucose and lipid metabolism, in inflammatory status, and in faecal Clostridia and Gammaproteobacteria abundance. Striking differences were also observed in the degree of statistical links between these measures, using newly developed correlation network analyses, implying that a rapid and inter-connected systems response was required for effective parasitic elimination.
This project also represents the first study to provide a comprehensive description of host metabolic changes in HAT. A total of 16 and 31 significant discriminatory metabolites were determined in plasma via 1H NMR spectroscopy and ultra-performance liquid chromatography/mass spectrometry (UPLC-MS), respectively, including membrane phospholipids and amino acids, linked with inflammation. These findings provide a unique insight into underlying metabolic interactions that may contribute to pathology, and reveal a set of infection-related markers with possible diagnostic potential for CL and HAT.
Version
Open Access
Date Issued
2015-11
Date Awarded
2016-02
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Holmes, Elaine
Saric, Jasmina
Sponsor
Medical Research Council (Great Britain); Welcome Trust (London, England)
Grant Number
MRC-DTA G1000390
Welcome Trust Sir Henry Fellowship project grant 082786
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)