Abstract
Pathophysiology of visceral leishmaniasis (VL) is not fully understood and it has been widely accepted that the parasitic components and host immune response both contribute to the perpetuation of the disease. Host alterations during leishmaniasis is a feebly touched area that needs to be explored more to better understand the VL prognosis and diagnosis, which are vital to reduce mortality and post-infection sequelae. To address this, we performed untargeted metabolomics of Leishmania donovani (Ld) infected, uninfected and treated BALB/c mice’s tissues and biofluids to elucidate the host metabolome changes using gas chromatography–mass spectrometry. Univariate and multivariate data treatments provided numerous significant differential hits in several tissues like the brain, liver, spleen and bone marrow. Differential modulations were also observed in serum, urine and fecal samples of Ld-infected mice, which could be further targeted for biomarker and diagnostic validations. Several metabolic pathways were found to be upregulated/downregulated in infected (TCA, glycolysis, fatty acids, purine and pyrimidine, etcetera) and treated (arginine, fumaric acid, orotic acid, choline succinate, etcetera) samples. Results also illustrated several metabolites with different pattern of modulations in control, infected and treated samples as well as in different tissues/biofluids; for e.g. glutamic acid identified in the serum samples of infected mice. Identified metabolites include a range of amino acids, saccharides, energy-related molecules, etcetera. Furthermore, potential biomarkers have been identified in various tissues—arginine and fumaric acid in brain, choline in liver, 9-(10) EpOME in spleen and bone marrow, N-acetyl putrescine in bone marrow, etcetera. Among biofluids, glutamic acid in serum, hydrazine and deoxyribose in urine and 3-Methyl-2-oxo pentanoic acid in feces are some of the potential biomarkers identified. These metabolites could be further looked into for their role in disease complexity or as a prognostic marker. The presented profiling approach allowed us to attain a metabolic portrait of the individual tissue/biofluid modulations during VL in the host and represent a valuable system readout for further studies. Our outcomes provide an improved understanding of perturbations of the host metabolome interface during VL, including identification of many possible potential diagnostic and therapeutic targets.
Highlights
Visceral leishmaniasis (VL) is a systemic disease that shows varied clinical manifestations and homing of the pathogen i.e. Leishmania to different visceral organs like liver and spleen further affecting bone marrow and brain (Melo et al, 2017; Burza et al, 2018)
Earlier studies have focused on cellular modifications in vitro, but it is still lagging in the in vivo assessment, so as to address the detailed trend of composition and heterogeneity of host during visceral leishmaniasis (VL) (Lamour et al, 2012)
The study reported here is mainly concerned with the identification of BALB/c metabolic alterations during Leishmania infection in several tissues like the brain, liver, spleen, bone marrow and biofluids like urine, serum and feces (Figure 1)
Summary
Visceral leishmaniasis (VL) is a systemic disease that shows varied clinical manifestations and homing of the pathogen i.e. Leishmania to different visceral organs like liver and spleen further affecting bone marrow and brain (Melo et al, 2017; Burza et al, 2018). Detection of differential or unique metabolites in various tissues could provide information to explain the pathophysiological stage of VL and can be even more useful in dealing with relapses. This method would be more beneficial as well as less expensive in diagnosing and treating VL
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