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Manuel Llinás

Research Focus


It is estimated that 40% of the worlds population lives in regions exposed to malaria, resulting in over 500 million cases and 3-5 million deaths annually. Malaria is caused by the parasites of the genus Plasmodium of which Plasmodium falciparum is the deadliest species. As such it is one of the most predominant eukaryotic human pathogens known. While strategies to eradicate malaria through mosquito control have worked successfully in First World nations, the associated cost of these programs has prevented global success. Furthermore, the widespread use of current therapeutic anti-malarial drugs has resulted in the sharp rise of resistant parasites in virtually all malaria-endemic areas. One of the major challenges facing this disease is the identification of new drug targets for efficacious, cost-effective therapeutic treatments. However, there is currently an overwhelming paucity of well-defined therapeutic targets, despite a genome containing over 5400 genes.

The genome sequence of Plasmodium falciparum reveals that this deadly organism is biochemically highly unique: 60% of its genome encodes proteins never seen before in biology, and the remaining 40% contains very few of the fundamental metabolic genes found in almost all other eukaryotes. Remarkably, only 8% of the Plasmodium genome is assigned to known metabolic pathways, while most other eukaryotic microbes devote roughly twice that amount of their genome to metabolism (e.g., 17% in the yeast Saccharomyces cerevisiae). This suggests that either the overall pathway structure of Plasmodium metabolism is quite different from commonly studied organisms, or that Plasmodial enzymes are highly divergent and not readily recognized. This uniqueness provides much needed new opportunities to kill this parasite by targeting novel metabolic pathways utilized solely by Plasmodium. Because new pathways or highly divergent enzymes provide ideal targets for pharmacological intervention, these sequence-based revelations point to major opportunities to improve global malaria treatment.

A major challenge in developing drug therapies is typically moving from a protein target to an effective, inexpensive small molecule drug. In this respect, targeting the metabolic network of Plasmodium has crucial advantages in that metabolic enzymes can often be targeted by close structural analogues of the natural enzyme substrate. These enzymes are central to every aspect of biology and metabolite levels (as substrates, products and co-factors) are the crucial read-out of the combined enzyme and transporter activity within cells. Right now, a primary barrier to developing new therapeutics against Plasmodium is lack of a basic science understanding of its metabolic network. A breakthrough in the ability to rapidly dissect metabolic networks has arisen from new advances in mass spectrometry and nuclear magnetic resonance (NMR). These advances enable for the first time almost comprehensive measurement of cellular metabolites. Because the flow of nutrients into versus out of these metabolites can be followed using isotope labeling, the structure and activity of poorly understood metabolic networks can be rapidly elucidated. The application of metabolomics, the global analysis of metabolite levels, to the study of the malaria parasite is rapidly becoming an important tool for understanding the host/parasite relationship. The resulting gains in metabolic knowledge will illuminate new targets for drug treatment, provide new medical diagnostics, unveil host-pathogen interactions, and identify nutritional imbalances induced by the parasite.

The Plasmodium pathogen relies on an exquisitely tuned interaction with the host red blood cell, usurping it for both immune evasion and metabolic precursor scavenging. Defining the metabolic interactions between the host red blood cell and this deadly pathogen presents a unique opportunity to reveal new biochemical pathways and elucidate potential drug targets. Ultimately, we would like to exploit this knowledge to establish novel antimalarial therapies based on enzymatic reactions and compounds identified in these studies. While our immediate interests are focused on malaria, the results of these studies have implications far beyond this disease, since several major agricultural parasites are Apicomplexan species whose biology remains virtually unexplored. This work will provide the missing link between the proteome and transcriptome, since metabolites ultimately are the genuine cellular readout.
 

Selected Recent Publications

  • van Brummelen AC, Olszewski KL, Wilinski D, LlináM, Louw AI, Birkholtz LM. "Co-inhibition of Plasmodium falciparum S-adenosylmethionine decarboxylase/ornithine decarboxylase reveals perturbation-specific compensatory mechanisms by transcriptome, proteome and metabolome analyses." (2008) J Biol Chem., 284 (7), pp. 4635-4646.
     
  • Olszewski KL, Morrisey JM, Wilinski D, Burns JM, Vaidya AB, Rabinowitz JD, LlináM. Host-parasite Interactions Revealed by Plasmodium falciparum Metabolomics (2009) Cell Host & Microbe, 5 (2), pp. 191-199. PMCID: PMC2737466
     
  • Kafsack BFC & LlináM. Eating at the Table of Another: Metabolomics of Host/Parasite Interactions. (2010) Cell Host & Microbe, 7 (2), pp. 90-99. PMCID: PMC2825149 (Available on 2011/2/18)
     
  • Olszewski KL, Mather MW, Morrisey JM, Garcia BA, Vaidya AB, Rabinowitz JD, LlináM. Branched Tricarboxylic Acid Metabolism in Plasmodium falciparum. (2010) Nature, accepted.
     

Manuel Llinás

Llinás Lab Webpage
mllinas@princeton.edu
Carl C. Ichan Laboratory, 246
Phone: 609-258-9391

Faculty Assistant:
Marybeth Fedel
fedele@princeton.edu
Carl C. Ichan Laboratory, 249
Phone: 609-258-7058