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The hunt for metabolite biomarkers of malaria
are involved in inflammation or are products of the gut microflora. One of the most interesting metabolites In the tropics, contact with mosquithat distinguished infected and unintoes must be avoided or minimized. fected urine samples was pipecolic That is because these stinging insects acid, says Holmes. “Pipecolic acid is can carry a wide range of viruses and not something you normally see at parasites that can cause severe illness appreciable levels in the urine specand even death. For example, malaria tra of mice or any mammal we’ve is a common infectious disease looked at,” she explains. caused by PlasmoOver the years, the redium parasites that searchers have collected spend part of their life data on various promiscycle in the Anopheles ing biomarkers for paramosquito. Every year, sitic infection, and they malaria is responsible are beginning to note for >1 million deaths some trends. Some meand >500 million clinitabolites are up- or cal disease episodes. down-regulated with any Although malaria is an parasitic infection comimportant public-health pared with controls, Possible markers. Orthogonal-projection to latent structure-discriminant analysis problem, that wasn’t the whereas others appear to (known as O-PLS-DA) coefficient plot for urine of mice infected with P. berghei. main reason Ju ¨ rg Utzbe specific to infection Pipecolic acid levels were higher in the urine of infected mice than in that of by a certain subtype of controls. inger of the Swiss Tropiparasite, such as worms cal Institute (STI) and or protozoa. Yet another Elaine Holmes of Impecategory of candidate markers seems When the group officially began the rial College London (ICL) started to pinpoint particular species, and malaria project in 2005, a validated studying the disease. During the past pipecolic acid fits in this class. mouse model for infection by P. falci6 years, the researchers’ groups have Now that a validated mouse model parum, the Plasmodium species that collaborated to better understand the for P. falciparum exists, the investigacauses most malaria deaths in hubiochemistry of several host-parasite tors plan to profile the metabolites of mans, did not exist. Therefore, the relationships. Utzinger explains that mice infected with this species. In scientists turned their attentions to P. their work with a malaria mouse addition, they would like to examine berghei, a species that causes malaria model “somehow just evolved” from urine and plasma samples from inin mice. Control urine and blood initial projects on parasitic worms. In fected humans to see whether the samples were obtained from mice beJPR (DOI 10.1021/pr800209d), potential biomarkers, such as pipefore they were infected. After mice Holmes, Utzinger, and colleagues at colic acid, identified in the mouse were injected with P. berghei-infected ICL, STI, University Hospital Basel study also appear in human subjects. red blood cells, samples were taken (Switzerland), and Princeton UniverAlthough the original goal of the at days 1, 2, 3, and 4 postinfection. sity describe the results of their foray project was to evaluate NMR-based To detect metabolic changes into the malaria field. They report metabolic profiling as a discovery caused by P. berghei infection, the that the levels of many metabolites tool for biomarkers of parasitic infecteam analyzed urine and plasma change after mice are infected with tion, the long-term goal is to apply samples with NMR spectroscopy. A the protozoan that causes malaria. this information to develop better standard 1D experiment was conWith metabolic profiling, the group diagnostics and therapies, says Utzducted on urine samples to obtain hoped to discover candidate biomarkinger. And it may take a while to reinformation on low-molecular-weight ers that could be used to diagnose maalize the long-term objectives. “This metabolites. Plasma was analyzed by laria, monitor patients’ responses to is a huge challenge, so we definitely 1D NMR, and then further analyses therapies, or find potential drug tarhave another 10-20 years of research were conducted specifically to detect gets. “Metabolic profiling has the adahead of us!” he points out. low- or high-molecular-weight comvantage that it gives a fingerprint of ponents. Several metabolites differenmany molecules simultaneously,” says tiated the control and postinfection —Katie Cottingham Holmes. “The more molecules you samples. Some of these metabolites have that are diagnostic of a particular
10.1021/pr8004716
disease, the more confident you are in your diagnosis.” Utzinger adds that current malaria diagnostics lack the necessary sensitivity and specificity, especially early in the disease process when parasite levels are low. Ultimately, the researchers would like to develop an inexpensive dipstick or labon-a-chip assay on the basis of the metabolic results they obtain.
© 2008 American Chemical Society
Journal of Proteome Research • Vol. 7, No. 9, 2008 3639
