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Parasitol Today,
1999]
Four years ago, a WHO/United Nations Development Programme/World Bank-sponsored genome project to study the filarial lymphatic nematode parasite Brugia malayi was initiated. The project took as its aims gene discovery for drug target and vaccine candidate identification, genome mapping, dissemination of genomic data to the world community and training of endemic country partners in genomic research. In this article, the principal investigators in the laboratories behind the project describe the background to the project, the data now emerging and goals for the future. Open access to filarial genome data is emphasized.
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Parasitology,
1999]
The initiation of genome projects on helminths of medical importance promises to yield new drug targets and vaccine candidates in unprecedented numbers. In order to exploit this emerging data it is essential that the user community is aware of the scope and quality of data available, and that the genome projects provide analyses of the raw data to highlight potential genes of interest. Core bioinformatics support for the parasite genome projects has promoted these approaches. In the Brugia genome project, a combination of expressed sequence tag sequencing from multiple DNA libraries representing the complete filarial nematode lifecycle, and comparative analysis of the sequence dataset, particularly using the complete genome sequence of the model nematode C. elegans, has proved very effective in gene discovery.
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Parasitology,
1999]
Genome projects for the parasitic helminths Brugia malayi (a representative filarial nematode) and Schistosoma were initiated in 1995 by the World Health Organization with the ultimate objectives of identifying new vaccine candidates and drug targets and of developing low resolution genome maps. Because no genetic maps are available, and very few genes have been characterized from either parasite group, the first goal of both Initiatives has been to catalogue new genes for future placement on chromosome and physical maps. These genes have been identified by the expressed sequence tag (EST) approach, utilising cDNA libraries constructed from diverse life cycle stages. To date, the Initiatives have deposited over 16,000 Brugia ESTs and nearly 8000 Schistosoma ESTs in Genbank's dbEST database, corresponding to 6000 and over 3600 genes respectively (33% of Brugia's estimated gene compliment, 18-24% of that of Schistosoma). Large fragment, genomic libraries have been constructed in BAC and YAC vectors for studies of genomic organization and for physical and chromosome mapping, and public, hypertext genomic databases have been established to facilitate data access. We present a summary of progress within the helminth genome initiatives and give several examples of important gene discoveries and future applications of these data.
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Parasitol Int,
2009]
Filarial nematode parasites, the causative agents of elephantiasis and river blindness, undermine the livelihoods of over one hundred million people in the developing world. Recently, the Filarial Genome Project reported the draft sequence of the ~95 Mb genome of the human filarial parasite Brugia malayi - the first parasitic nematode genome to be sequenced. Comparative genome analysis with the prevailing model nematode Caenorhabditis elegans revealed similarities and differences in genome structure and organization that will prove useful as additional nematode genomes are completed. The Brugia genome provides the first opportunity to comprehensively compare the full gene repertoire of a free-living nematode species and one that has evolved as a human pathogen. The Brugia genome also provides an opportunity to gain insight into genetic basis for mutualism, as Brugia, like a majority of filarial species, harbors an endosybiotic bacterium (Wolbachia). The goal of this review is to provide an overview of the results of genomic analysis and how these observations provide new insights into the biology of filarial species.
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Parasite Immunol
]
Filarial nematode parasites, the causative agents for a spectrum of acute and chronic diseases including lymphatic filariasis and river blindness, threaten the well-being and livelihood of hundreds of millions of people in the developing regions of the world. The 2007 publication on a draft assembly of the 95-Mb genome of the human filarial parasite Brugia malayi- representing the first helminth parasite genome to be sequenced - has been followed in rapid succession by projects that have resulted in the genome sequencing of six additional filarial species, seven nonfilarial nematode parasites of animals and nearly 30 plant parasitic and free-living species. Parallel to the genomic sequencing, transcriptomic and proteomic projects have facilitated genome annotation, expanded our understanding of stage-associated gene expression and provided a first look at the role of epigenetic regulation of filarial genomes through microRNAs. The expansion in filarial genomics will also provide a significant enrichment in our knowledge of the diversity and variability in the genomes of the endosymbiotic bacterium Wolbachia leading to a better understanding of the genetic principles that govern filarial-Wolbachia mutualism. The goal here is to provide an overview of the trends and advances in filarial and Wolbachia genomics.
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Trends Genet,
1998]
From their earliest experiments, researchers using Caenorhabditis elegans have been interested in the role of genes in the development and function of the nervous system. As the C. elegans Genome Project completes the genomic sequence, we review the accomplishments of these researchers and the impact that the Genome Project has bad on their research. We also speculate on future directions in this research that are enabled by the efforts of the Genome Project.
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Parasite Immunol,
2001]
Filarial nematodes are metazoan parasites with genome sizes of> 100 million base pairs, probably encoding 15 000-20 000 genes. Within this considerable gene complement, it seems likely that filariae have evolved a spectrum of immune evasion products which underpin their ability to live for many years within the human host. Moreover, no suitable vaccine currently exists for human filarial diseases, and few markers have yet been established for diagnostic use. In this review, we bring together biochemical and immunological data on prominent filarial proteins with the exciting new information provided by the Filarial Genome Project's expressed sequence tag (EST) database. In this discussion, we focus on those genes with the highest immunological profile, such as inhibitors of host enzymes, cytokine homologues and stage-specific surface proteins, as well as products associated with the mosquito-borne infective larva which offer the best opportunity for an anti-filarial vaccine. These gene products provide a fascinating glimpse of the molecular repertoire which helminth parasites have evolved to manipulate and evade the mammalian immune response.
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Ann N Y Acad Sci,
2003]
Filarial nematodes cause some of the most debilitating diseases in tropical medicine. Recent studies, however, have implicated the parasites' endosymbiotic Wolbachia bacteria, rather than the nematode, as the cause of inflammatory-mediated filarial disease. Soluble extracts of a variety of filarial species stimulate innate inflammatory responses, which are absent or reduced when using extracts derived from species either devoid of bacteria, or those cleared of bacteria by antibiotics. Characterization of the molecular nature of the bacterial derived inflammatory stimulus points toward an endotoxin-like activity that is dependent on the pattern recognition receptors CD14 and TLR4 and can be inhibited by lipid A antagonists. TLR4 dependent inflammation has been shown to occur in the systemic inflammatory adverse reaction to Brugia malayi following anti-filarial chemotherapy and in the development of neutrophil-mediated ocular inflammation in a mouse model of river blindness. The development of acute and severe inflammatory responses in people infected with Brugia malayi and Onchocerca volvulus is associated with the release of Wolbachia into the blood following death or damage of the worms after anti-filarial chemotherapy. Together these studies suggest that Wolbachia are the principal cause of acute inflammatory filarial disease. Accumulated exposure to acute episodes of inflammation may also underlie the development of chronic filarial pathology. The use of antibiotic therapy to target Wolbachia of filarial parasites may therefore provide a means to prevent the development of filarial pathology.
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Rev Infect Dis
]
This report summarizes the findings of the 17 published studies involving humans who have been experimentally infected with filarial parasites. Over the past 60 years, 45 individuals have been deliberately infected with Wuchereria bancrofti, Brugia malayi, Brugia pahangi, Loa loa, Mansonella perstans, Mansonella ozzardi, and/or Onchocerca volvulus. The findings from these experimental infections of humans have helped define microfilarial survival and periodicity within human hosts, the prepatent period for the causative agents of lymphatic filariasis, etiologic agents for particular clinical syndromes, immunologic and hematologic consequences of filarial infection, and the role of chemotherapeutic agents in the prevention and treatment of filarial infections.
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Endocr Metab Immune Disord Drug Targets,
2012]
Filarial infections are characterized by immunopathological phenomena, that are responsible for the onset of often dramatic pathological outcomes, such as blindness (Onchocerca volvulus) and elephantiasis (W. bancrofti). In addition, the long-term survival (as long as 10 years) of these parasites in otherwise immunocompetent hosts indicates that these nematodes are capable of manipulating the host immune response. The ground-breaking discovery of the bacterial endosymbiont Wolbachia, which resides in most filarial nematodes causing disease, has led to increasing interest in the role it may play in immuno-modulation, pro-inflammatory pathology and other aspects of filarial infection. Indeed, Wolbachia has been shown to be responsible for exacerbating inflammation (as in river blindness), while at the same time blocking efficient elimination of parasites through the host immune response (Onchocerca ochengi). While studies aimed at identifying Wolbachia as a potential target for anti-filarial therapy are at the forefront of current research, understanding its role in the immunology of filarial infection is a fascinating field that has yet to uncover many secrets.