Vladimir Likic: bioinformatics and systems biology

My research interests are in microbial pathogens, and how to improve control and management of diseases caused by microbial organisms. I collaborate with Macolm McConville (Professor, Department of Biochemistry and Molecular Biology, University of Melbourne) on understanding of metabolic networks in Leishmania parasites, and Trevor Lithgow (Professor & ARC Federation Fellow, Department of Biochemistry and Molecular Biology, Monash University) on understanding of how pathogenic microbes deliver toxic proteins to their hosts. I lead bioinformatics activities in Metabolomics Australia, a national service centre for metabolomics funded by the National Collaborative Research Infrastructure Strategy (NCRIS), State Governments, and host institutions.

Metabolic networks in Leishmania parasites

Metabolism is the chemical engine that powers life: metabolic networks consist of a large number of coupled chemical reactions that supply cells with energy, assemble macromolecules from amino acids and nucleotides, and supply a variety of intermediates required for sustained operations of the cellular machinery. Metabolic pathways are individual sequences of enzymatic reactions that interconvert chemical species, and represent conceptual building blocks of metabolic networks (for an idea about metabolic pathways, see the metabolic pathways map, copyright the International Union of Biochemistry and Molecular Biology, and provided by Sigma Aldrich)

Species of the genus Leishmania are parasitic protozoa transmitted by sand flies that cause leishmaniasis, the devastating disease in tropical and sub-tropical parts of the world. Leishmania infections cause a range of symptoms in humans, from skin lesions and ulcers (cutaneous leishmaniasis), to severe facial disfiguring (mucocutaneous leishmaniasis), and visceral forms (visceral leishmaniasis, also known as kala azar) which is fatal if untreated. It is estimated that more than 12 million people are infected with Leishmania, with 350 million people at risk. This makes Leishmania the most important parasitic pathogen after Plasmodium (the parasite which causes malaria). There is no vaccine against leishmaniasis, and current treatments of are highly toxic, costly, with increasing drug resistance. For more information please see the World Health Organisation: Leishmaniasis or search the net. (Warning: graphic images!). Leishmania belongs to the family Trypanosomatidae, which also includes organisms from genera Trypanosma. Trypanosomas T. brucei and T. cruzi are highly infective to humans, and cause sleeping sickness (African trypanosomiasis) and Chagas disease (American trypanosomiasis).

Better understanding of metabolic networks in Leishmania is the key to better control and management of infections in humans and domestic animals caused by these parasites. My group leads the development of the integrated database of Leishmania metabolic pathways (LeishCyc). This is a pathway-genome database based on the BioCyc ontology, the first such database for any of the Trypanosomatidae parasites. I am collaborating with Macolm McConville on elucidation of Leishmania metabolic networks through the application of metabolomics, metabolic flux analysis, and metabolic reconstruction.

Bacterial secretion systems

Gram-negative bacteria have developed a number of specialised secretion mechanisms to facilitate interactions with their hosts, and in particular for the secretion of toxins and effectors (disease-causing molecules). These mechanisms rely on elaborate protein-protein interactions and specialised structural features to facilitate translocation of proteins across cell membranes. At least six distinct types of secretion systems have been identified to date, termed Type I to Type VI secretion systems. For example, Type III secretion systems translocate special proteins into the cytosol of eukaryotic cells, where they interfere with cellular signal transduction processes. Likewise, Type V secretion systems have been associated with various virulence activities including cell adhesion, invasion, and secretion of toxins which play important roles in pathogenesis.

Bacterial secretion systems are elaborate molecular machines (see for example here). I collaborate with Trevor Lithgow ( Department of Biochemistry and Molecular Biology, Monash University) on the elucidation of structure and mechanisms of bacterial secretion systems. We are interested in protein transport machines in bacteria and in mitochondria. Mitochondria are found in eukaryotic cells, often several or many per cell. Mitochondria are descendants of a bacterial endosymbiont, as they evolved from primitive bacteria had a symbiotic relationship with early eukaryotic cells.

Selected publications

Saunders EC, Ng WW, Chambers JM, Ng M, Naderer T, Krömer JO, Likic VA, McConville MJ, Isotopomer Profiling of Leishmania mexicana Promastigotes Reveals Important Roles for Succinate Fermentation and Aspartate Uptake in Tricarboxylic Acid Cycle (TCA) Anaplerosis, Glutamate Synthesis, and Growth, J Biol Chem, 286(31):27706-17. Epub 2011 Jun 2. PMID: 21636575. (2011). (link to abstract)

Likic VA, McConville MJ, Lithgow T, Bacic A, Systems Biology: The Next Frontier for Bioinformatics, Advances in Bioinformatics, Volume 2010, Article ID 268925, doi:10.1155/2010/268925 (2010). ( link to article)

Saunders EC, DE Souza DP, Naderer T, Sernee MF, Ralton JE, Doyle MA, Macrae JI, Chambers JL, Heng J, Nahid A, Likic VA, McConville MJ, Central carbon metabolism of Leishmania parasites, Parasitology, 2010 Feb 17:1-11. [Epub ahead of print]

Likic VA, Extraction of pure components from overlapped signals in gas chromatography-mass spectrometry (GC-MS), BMC BioData Mining, 2(1):6 (2009). (link to article)

Doyle MA, MacRae JI, De Souza DP, Saunders EC, McConville MJ, and Likic VA, LeishCyc: a biochemical pathways database for Leishmania major, BMC Systems Biology, 3:57 (2009) (link to article)

Robinson MD, De Souza DP, Keen WW, Saunders EC, McConville MJ, Speed TP, Likic VA, A dynamic programming approach for the alignment of signal peaks in multiple gas chromatography-mass spectrometry experiments, BMC Bioinformatics, 8:419 (2007).

McConville MJ, de Souza D, Saunders E, Likic VA, Naderer T, Living in a phagolysosome; metabolism of Leishmania amastigotes, Trends Parasitol. 2007 Jun 30; [Epub ahead of print] PMID: 17606406

Gentle IE, Perry AJ, Alacock FH, Likic VA, Dolezal P, Ng E, Purcell AW, McConville MJ, Naderer T, Chanez AL, Charriere F, Aschinger C, Schneider A, Tokatlidis K, Lithgow T, Conserved motifs reveal details of ancestry and structure in the small TIM chaperones of the mitochondrial intermembrane space, Molecular Biology and Evolution, Feb 2007 [Epub ahead of print], PMID: 17329230.

Dolezal P, Likic VA, Tachezy J, and Lithgow T, Evolution of the Molecular Machines for Protein Import into Mitochondria, Science 313: 314-318 (2006).

DeSouza DP, Saunders EC, McConville MJ, Likic VA, Progressive Peak Clustering in GC-MS Experiments Applied to Leishmania Parasites, Bioinformatics 22(11):1391-6 (2006)