The application of functional genomics, systems biology and drug development to the study of infectious diseases

Genomics is creating a paradigm shift in the research of infectious diseases, transforming it from studying a few targets at a time to a genomic scale. We applied three genomic approaches to the study of malaria and its causative agents, a type of intracellular parasites belonging to the genus Plasmodium.; The first approach was to use DNA microarray technology to study the parasite transcriptome. The peculiarity of the P. falciparum genome made it difficult to produce a traditional cDNA probe-based microarray. We introduced a long oligonucleotide-based system in which each probe uniquely represents a single open reading frame and is optimized for other parameters including sequence complexity, secondary structure, and melting temperature. In order to produce such an optimal set of probes, we developed ArrayOligoSelector to automatically select gene specific long oligonucleotide probes for a complete genome.; In addition to study the parasite transcriptome, we developed a virtual drug development framework to identify anti-malarial compounds. The framework started with complete genome sequences and resulted in potential antimalarials; in the process it integrated a diverse and large amount of informatics data and computational methods. Using this framework, we identified 152 drug target genes by mining the phylogenomic patterns of 203 genomes and 77 co-ligands of those target proteins by comparative protein structure modeling and enzymatic predictions. Using the co-ligands as queries, we have computationally screened large compound collections to identify 1892 "drug-like" compounds that are structurally similar as well as commercially available.; Our third genomic strategy was to explore host pathogen interactions. We chose to focus on the pathogenic response to nitric oxide. Nitric oxide is an important mediator in the human innate immune response and a molecule associated with protection against severe malaria. The host innate immune response defends against infection by a wide range of pathogens including fungi and protozoan parasites. Since it is much easier to perform large-scale functional genomics experiments in a model organism other than in Plasmodium, we characterized the nitric oxide response in S. cerevisiae and applied a Bayesian network-driven approach to model the transcriptional response in that system.