Metabolic profiling framework for discovery of candidate diagnostic markers of malaria.
Despite immense efforts to combat malaria in tropical and sub-tropical regions, the potency of this vector-borne disease and its status as a major driver of morbidity and mortality remain undisputed. We develop an analytical pipeline for characterizing Plasmodium infection in a mouse model and identify candidate urinary biomarkers that may present alternatives to immune-based diagnostic tools. We employ (1)H nuclear magnetic resonance (NMR) profiling followed by multivariate modeling to discover diagnostic spectral regions. Identification of chemical structures is then made on the basis of statistical spectroscopy, multinuclear NMR, and entrapment of candidates by iterative liquid chromatography (LC) and mass spectrometry (MS). We identify two urinary metabolites (i) 4-amino-1-[3-hydroxy-5-(hydroxymethyl)-2,3-dihydrofuran-2-yl]pyrimidin-2(1H)-one, (ii) 2-amino-4-({[5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4-hydroxy-4,5-dihydrofuran-2-yl]methyl}sulfanyl)butanoic acid that were detected only in Plasmodium berghei-infected mice. These metabolites have not been described in the mammalian or parasite metabolism to date. This analytical pipeline could be employed in prospecting for infection biomarkers in human populations.
1] Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland [2] University of Basel, CH-4003 Basel, Switzerland.
Lucienne
L
Tritten
Jennifer
J
Keiser
Markus
M
Godejohann
Jürg
J
Utzinger
Mireille
M
Vargas
Olaf
O
Beckonert
Elaine
E
Holmes
Jasmina
J
Saric
D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D001835:Body Weight; D060085:Coinfection / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000469:parasitology; D004195:Disease Models, Animal; D005260:Female; D006369:Heligmosomatoidea / Q000502:physiology; D006400:Hematocrit; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008288:Malaria / Q000150:complications / Q000175:diagnosis* / Q000378:metabolism* / Q000469:parasitology; D055442:Metabolome; D055432:Metabolomics; D051379:Mice; D010962:Plasmodium berghei / Q000502:physiology; D017206:Strongylida Infections / Q000097:blood / Q000150:complications / Q000469:parasitology / Q000652:urine
D015415:Biomarkers