Journal
PLOS ONE
Volume 8, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0060840
Keywords
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Categories
Funding
- John A. Burns School of Medicine
- Department of Defense (DOD) [W81XWH-07-2-0073]
- Research Centers in Minority Institutions Program, National Center for Research Resources (NCRR), National Institutes of Health (NIH) [G12RR003061]
- Research Centers in Minority Institutions Translational Research Network, National Center for Research Resources (NCRR), National Institutes of Health (NIH) [U54RR022762]
- Research Centers in Minority Institutions Multidisciplinary and Translational Research Infrastructure Expansion, National Center for Research Resources (NCRR), National Institutes of Health (NIH) [U54RR026136]
- Centers of Biomedical Research Excellence, National Center for Research Resources (NCRR), National Institutes of Health (NIH) [P20RR018727]
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Malaria is a global infectious disease that threatens the lives of millions of people. Transcriptomics, proteomics and functional genomics studies, as well as sequencing of the Plasmodium falciparum and Homo sapiens genomes, have shed new light on this host-parasite relationship. Recent advances in accurate mass measurement mass spectrometry, sophisticated data analysis software, and availability of biological pathway databases, have converged to facilitate our global, untargeted biochemical profiling study of in vitro P. falciparum-infected (IRBC) and uninfected (NRBC) erythrocytes. In order to expand the number of detectable metabolites, several key analytical steps in our workflows were optimized. Untargeted and targeted data mining resulted in detection of over one thousand features or chemical entities. Untargeted features were annotated via matching to the METLIN metabolite database. For targeted data mining, we queried the data using a compound database derived from a metabolic reconstruction of the P. falciparum genome. In total, over one hundred and fifty differential annotated metabolites were observed. To corroborate the representation of known biochemical pathways from our data, an inferential pathway analysis strategy was used to map annotated metabolites onto the BioCyc pathway collection. This hypothesis-generating approach resulted in over-representation of many metabolites onto several IRBC pathways, most prominently glycolysis. In addition, components of the branched TCA cycle, partial urea cycle, and nucleotide, amino acid, chorismate, sphingolipid and fatty acid metabolism were found to be altered in IRBCs. Interestingly, we detected and confirmed elevated levels for cyclic ADP ribose and phosphoribosyl AMP in IRBCs, a novel observation. These metabolites may play a role in regulating the release of intracellular Ca2+ during P. falciparum infection. Our results support a strategy of global metabolite profiling by untargeted data acquisition. Untargeted and targeted data mining workflows, when used together to perform pathway-inferred metabolomics, have the benefit of obviating MS/MS confirmation for every detected compound.
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