Date Published: September 24, 2008
Publisher: Public Library of Science
Author(s): Shivashankar H. Nagaraj, Robin B. Gasser, Shoba Ranganathan, Michael Cappello
Abstract: BackgroundParasitic nematodes of humans, other animals and plants continue to impose a significant public health and economic burden worldwide, due to the diseases they cause. Promising antiparasitic drug and vaccine candidates have been discovered from excreted or secreted (ES) proteins released from the parasite and exposed to the immune system of the host. Mining the entire expressed sequence tag (EST) data available from parasitic nematodes represents an approach to discover such ES targets.Methods and FindingsIn this study, we predicted, using EST2Secretome, a novel, high-throughput, computational workflow system, 4,710 ES proteins from 452,134 ESTs derived from 39 different species of nematodes, parasitic in animals (including humans) or plants. In total, 2,632, 786, and 1,292 ES proteins were predicted for animal-, human-, and plant-parasitic nematodes. Subsequently, we systematically analysed ES proteins using computational methods. Of these 4,710 proteins, 2,490 (52.8%) had orthologues in Caenorhabditis elegans, whereas 621 (13.8%) appeared to be novel, currently having no significant match to any molecule available in public databases. Of the C. elegans homologues, 267 had strong “loss-of-function” phenotypes by RNA interference (RNAi) in this nematode. We could functionally classify 1,948 (41.3%) sequences using the Gene Ontology (GO) terms, establish pathway associations for 573 (12.2%) sequences using Kyoto Encyclopaedia of Genes and Genomes (KEGG), and identify protein interaction partners for 1,774 (37.6%) molecules. We also mapped 758 (16.1%) proteins to protein domains including the nematode-specific protein family “transthyretin-like” and “chromadorea ALT,” considered as vaccine candidates against filariasis in humans.ConclusionsWe report the large-scale analysis of ES proteins inferred from EST data for a range of parasitic nematodes. This set of ES proteins provides an inventory of known and novel members of ES proteins as a foundation for studies focused on understanding the biology of parasitic nematodes and their interactions with their hosts, as well as for the development of novel drugs or vaccines for parasite intervention and control.
Partial Text: Molecules secreted by a cell, often referred to excretory/secretory (ES) products, play pivotal biological roles across a diverse range of taxa, ranging from bacteria to mammals . ES proteins can represent 8±20% of the proteome of an organism ,. ES proteins include functionally diverse classes of molecules, such as cytokines, chemokines, hormones, digestive enzymes, antibodies, extracellular proteinases, morphogens, toxins and antimicrobial peptides. Some of these proteins are known to be involved in vital biological processes, including cell adhesion, cell migration, cell-cell communication, differentiation, proliferation, morphogenesis and the regulation of immune responses . ES proteins can circulate throughout the body of an organism (in the extracellular space), are localized to or released from the cell surface, making them readily accessible to drugs and/or the immune system. These characteristics make them attractive as targets for novel therapeutics, which are currently the focus of major drug discovery research programmes . For example, knowledge of the molecular basis of secretory pathways in bacteria has facilitated the rational design of heterologous protein production pathways in biotechnology and in the development of novel antibiotics. From a more fundamental perspective, proteins secreted by pathogens are of particular interest in relation to the pathogen-host interactions, because they are present or active at the interface between the parasite and host cells, and can regulate the host response and/or cause disease ,.