Parasitic roundworms (called nematodes, a form of helminth) have a major, long-term impact on human health and cause substantial suffering, particularly in children. The parasites’ infection of animals and crops worldwide also has a major impact on the economy and exacerbates the global food shortage. The McDonnell Genome Institute is using integrated approaches to help develop more efficient and sustainable parasitic nematode control programs.
Nematodes diverged evolutionarily from other animals between 600-1200 million years ago, adapting a number of phyla-specific features along the way. Proteins with specificity to nematodes may serve as excellent drug targets with low toxicity to humans and other vertebrates or as environmentally safe pesticides. Guided by the importance of identifying nematode-specific proteins and aided by the increase of nematode sequences in public databases, we have created computational-based methods that can detect highly conserved regions in a robust fashion. Our approach has identified putative coding sequences conserved across the phylum Nematoda or nematode subgroups. We are doing extensive functional and structural characterization of all identified nematode-specific protein families, and several are being characterized in more detail with an emphasis on postulating molecular or cellular function.
The nematode intestine is a major organ responsible for nutrient digestion and absorption; it is also involved in many other processes such as reproduction, immunity, stress response, and aging. Recently, the intestine has become an effective control target against parasitic nematodes. However, the lack of gene and gene expression information from the intestine has impeded breakthroughs. We have sampled various transcribed genomes from the intestines of several parasitic nematode species and have created the largest collection of intestine-expressed genes for any parasitic nematode. Cross-species comparison to the intestine of free-living adult C. elegans is underway to investigate conservation of intestinal gene expression at the tissue level across the nematodes. Our study aims to provide novel insights into the nematode intestine and lay the foundation for further comparative studies on biology, parasitism, and evolution within the phylum Nematoda.
Parasitic nematodes infect over half the world's population, resulting in significant morbidity and mortality. Characterization of nematode genomes provides fundamental molecular information about these parasites, accelerating basic research and development of new diagnostics and therapeutics. Washington University’s McDonnell Genome Institute has generated and made public over 400,000 cDNAs from 30 parasitic species, sequenced 4 genomes to draft coverage with ten more underway including representatives of the major human parasitic groups. The three aims of this project analyze the expanding nematode sequences to substantially improve understanding of parasitic nematode biology and cellular pathways. First, we develop and use bioinformatic tools to process, assemble, and annotate incoming data from all sequencing platforms. These genomic resources will also be disseminated to the wider research community through the centralized parasitic nematode database, nematode.net. Second, we focus analysis on biochemical pathways that are conserved and/or taxonomically restricted, including proteins that may prove useful as drug targets. Third, we study the nature and implications of nematode-specific insertions and deletions in proteins involved in environmental information processing and the endocrine system. The expected outcome will facilitate and promote the discovery and development of novel interventions to control these important parasites and reduce their associated morbidity and mortality.
Helminth infections are estimated to have a disease burden equivalent to 25% of that of HIV/AIDS and 50% of that of malaria. Due to this enormous health burden there is now an unprecedented effort – based on mass drug administration of very few anthelmintic drugs – to control these infections. However, re-infection after drug therapy is common and anthelmintic resistance is emerging and spreading as a problem. We seek to sequence the genomes and transcriptomes of anthelmintic resistant strains to provide an essential resource for a better understanding of the genome diversity and mechanisms of resistance in human helminths. The genome sequences of anthelmintic susceptible and multiple anthlemintic resistant strains of a model parasite, Telodorsagia circumcincta, will enable identification of genetic and expression changes related to anthelmintic resistance. Sequencing the genomes of susceptible and clinical isolates resistant to helminth infections (human hookworm, Necator americanus) will enable generation of resistance-associated variant maps and will provide resources to identify mutations and indels in genes subject to recent natural selection in the human parasites. Similarly, comparison of expression profiles will identify putative changes related to resistance. The genome sequencing of a susceptible T. circumcincta strain and the human hookworm, N. americanus are underway (funded by NHGRI). Genomes of drug resistant isolates will provide the helminth research community with the resources needed to create a comprehensive map of genetic diversity in a model parasite and will inform similar studies involving parasites of importance in humans. In the long run, this work will enable a deeper understanding of the potential resistance mechanisms in human parasites and aid in the identification of genetic markers for the monitoring and management of the development and spread of resistance.
For more details on our nematode research please visit www.nematode.net.