Metabolic Fingerprints of Serum, Brain, and Liver Are Distinct for Mice with Cerebral and Noncerebral Malaria: A ¹H NMR Spectroscopy-Based Metabonomic Study

Abstract

Cerebral malaria (CM) is a life-threatening disease in humans caused by Plasmodium falciparum, leading to high mortality. Plasmodium berghei ANKA (PbA) infection in C57Bl/6 mice induces pathologic symptoms similar to that in human CM. However, experimental CM incidence in mice is variable, and there are no known metabolic correlates/ fingerprints for the animals that develop CM. Here, we have used 1 H NMR-based metabonomics to investigate the metabolic changes in the mice with CM with respect to the mice that have noncerebral malaria (NCM) of the same batchmates with identical genetic backgrounds and infected simultaneously. The metabolic profile of the infected mice (both CM and NCM) was separately compared with the metabolite profile of uninfected control mice of same genetic background. The objective of this study was to search for metabolic changes/fingerprints of CM and identify the pathways that might be differentially altered in mice that succumbed to CM. The results show that brain, liver, and sera exhibit unique metabolic fingerprints for CM over NCM mice. Some of the major fingerprints are increased level of triglycerides, VLDL-cholesterol in sera of CM mice, and decreased levels of glutamine in the sera concomitant with increased levels of glutamine in the brain of the mice with CM. Moreover, glycerophosphocholine is decreased in both the brain and the liver of animals with CM, and myo-inositol and histamine are increased in the liver of CM mice. The metabolic fingerprints in brain, sera, and liver of mice with CM point toward perturbation in the ammonia detoxification pathway and perturbation in lipid and choline metabolism in CM specifically. The study helps us to understand the severity of CM over NCM and in unrevealing the specific metabolic pathways that are compromised in CM.

Glycerophosphocholine Utilization by Candida albicans

“…Upon reintegration of GDE1, internal metabolites returned to levels similar to wild type. These results indicate that both Git3 and Gde1 are active in the presence of serum, which is known to contain GroPCho (14,15,43).…”

The metabolomic window into hepatobiliary disease

“…Metabolomic studies have been reported that are of relevance to Wilson's disease [103, 104], primary biliary cirrhosis [105], primary sclerosing cholangitis [105], the hepatic stage of malaria [106–108], as well as various aspects of hepatic encephalopathy [109–112]. …”

Metabolome-wide association study of peripheral parasitemia in Plasmodium vivax malaria

“…Nuclear magnetic resonance or gas/liquid chromatography coupled with mass spectrometry (GC/LC-MS) have been applied to understand the metabolic changes in models of host- Plasmodium interactions in vitro (Lakshmanan et al, 2012; MacRae et al, 2013; O’Hara et al, 2014; Olszewski et al, 2009; Park et al, 2015; Sana et al, 2013) and in vivo (Basant et al, 2010; Ghosh et al, 2012, 2013; Olszewski et al, 2009; Sengupta et al, 2013; Tritten et al, 2013). However, studies of human malaria are limited to evaluation of plasma from patients infected with P. falciparum (Lakshmanan et al, 2012; Surowiec et al, 2015; Sengupta et al, 2016) or urine from patients infected with P. vivax (Sengupta et al, 2011).…”