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[
Int J Parasitol,
2003]
Onchocerciasis is a major filarial disease and is the second most common cause of infectious blindness in the world. Disease development after infection with Onchocerca volvulus varies widely and is determined by the host's immune response to the parasite. Vector control and administration of ivermectin has reduced infection and disease rates significantly. However, limitations of these programmes, including ivermectin's selective activity on microfilariae, the need for 10-15 years of annual treatments, logistical obstacles and the potential emergence of drug-resistant strains demand alternative strategies. A vaccine that targets O. volvulus infective third-stage larvae (L3) could provide an additional tool to guarantee successful elimination of infection with O. volvulus. An essential step in the development of immunoprophylactic procedures and reagents is the identification of host immune responses toward antigens of O. volvulus L3 and L3 developing to the fourth-stage larvae that are associated with protection against these stages of the parasite. This review summarises the recent advancements in understanding the immune mechanisms in particular the CD4(+) responses to L3 stages in humans and in the mouse vaccination model. Comparison between the two uncovered common immunological elements in naturally exposed humans and mice vaccinated with radiation attenuated L3 or recombinant O. volvulus antigens, as well as significant differences. These studies promisingly suggest that the O. volvulus mouse model is a very useful adjunct to the studying of natural infection in humans and could provide us with the tools to identify the target molecules and the effector immune correlates of protection in humans responsible for attrition of L3 stages. Since some of these antigens may exist in other nematodes, any insight gained into the mechanisms of vaccine-induced anti-O. volvulus L3 protective immunity in both humans and mice could be applicable to the development of vaccines against other nematode infections.
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[
Exp Parasitol,
1998]
Recent work from Riddle and coworkers has shown that in the free-living soil nematode, Caenorhabditis elegans, the decision to become a developmentally arrested, dispersal form known as the dauer ("enduring") larva is controlled, at least in part, by transcription of a wild-type allele at the
daf-7 locus.
daf-7 mutants are "constitutive dauers." Using this model as a general paradigm for nematode development, I propose that many nematode parasites behave as though they were
daf-7 mutants. This will ensure developmental arrest at the L3 stage. I further propose that these organisms obtain the
daf-7 gene product required for reentry into the developmental pathway from the mammalian host and that their tissue localization is dictated by the
daf-7 homologue that is uniquely recognized by the cognate receptor.
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[
Stadler Genetics Symposium,
1977]
C. elegans is a roundworm, a free-living soil nematode. The dauer larva is a non-feeding, non-growing larval stage which is formed under conditions of starvation. It possesses a relatively impermeable cuticle and differs from all other larval stages in behavior and morphology. Dauer larva formation is a "developmental switch" in the life cycle which offers special advantages for genetic study. A partial genetic pathway for dauer larva formation has been established. Genetic characterization of additional mutants should reveal more details of this pathway. One class of mutants already characterized exhibits morphological alterations in sensory neurons, as determined by electron microscopy. Such mutants are useful for the study of nerve morphogenesis.
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[
Parasitology,
2000]
The bovine parasite Onchocerca ochengi is a nodule-dwelling filarial nematode, closely related to O. volvulus, the causal agent of human River Blindness, and, sharing with it, the same vector. This brief review, based on a presentation at the BSP Autumn Symposium 1999, describes recent work supported by the WHO Drug Development Research Macrofil programme and the Edna McConnell Clark Foundation vaccine development programme, to research the chemotherapy and immunology of onchocerciasis utilising this model system, with experimental infections in Liverpool and field infections in northern Cameroon. In a series of chemotherapeutic trials involving 10 compounds in 20 treatment regimes, the comparability of drug efficacy against O. ochengi with that described against O. volvulus has been demonstrated. Repeated, long-term treatment with oxytetracycline has been shown to be macrofilaricidal and the effect is hypothesized to be related to action on Wolbachia endobacteria, abundant in O. ochengi. Avermectins/milbemycins are not macrofilaricidal (even in high and repeated long-term treatments) but induce sustained abrogation of embryogenesis. In prospective, field exposure experiments with naive calves, prophylactic treatments with ivermectin and moxidectin prevented the development of adult worm infection, raising the possibility that drug-attenuated larval challenge infections may induce immunity. Putatively immune adult cattle exist in endemically exposed populations, and these have been shown to be significantly less susceptible to challenge than age-matched naive controls, whereas radically drug-cured, previously patently-infected cattle were not. Experimental infections with O. ochengi have revealed the kinetics of the immune response in relation to parasite development and demonstrate analogous responses to those reported in O. volvulus infection in humans and chimpanzees. In an immunization experiment with irradiated L3 larvae, cattle were significantly protected against experimental challenge--the first such demonstration of the experimental induction of immunity in a natural Onchocerca host-parasite system. Taken collectively, these studies not only demonstrate the similarity between the host-parasite relationships of O. ochengi in cattle and O. volvulus in humans, but promise to advance options for the control of human onchocerciasis.
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[
Curr Biol,
2005]
Despite low global diversity among natural populations of Caenorhabditis elegans, neighboring populations can be as genetically distinct as strains from different continents, probably owing to transient bottlenecks and ongoing dispersal as a dauer larva. Selfing predominates in the wild, but rare outcrossing may also play an important role.
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Schnieder T, Campbell BE, Gasser RB, Sternberg PW, Young ND, Hall RS, Jex AR, Cantacessi C, Mitreva M, Ranganathan S, Strube C
[
Biotechnol Adv,
2010]
The lungworm, Dictyocaulus viviparus, causes parasitic bronchitis in cattle, and is responsible for substantial economic losses in temperate regions of the world. Here, we undertake the first large-scale exploration of available transcriptomic data for this lungworm, examine differences in transcription between different stages/both genders and identify and prioritize essential molecules linked to fundamental metabolic pathways, which could represent novel drug targets. Approximately 3 million expressed sequence tags (ESTs), generated by 454 sequencing from third-stage larvae (L3s) as well as adult females and males of D. viviparus, were assembled and annotated. The assembly of these sequences yielded ~61,000 contigs, of which relatively large proportions encoded collagens (4.3%), ubiquitins (2.1%) and serine/threonine protein kinases (1.9%). Subtractive analysis in silico identified 6928 nucleotide sequences as being uniquely transcribed in L3, and 5203 and 7889 transcripts as being exclusive to the adult female and male, respectively. Most peptides predicted from the conceptual translations were nucleoplasmins (L3), serine/threonine protein kinases (female) and major sperm proteins (male). Additional analyses allowed the prediction of three drug target candidates, whose Caenorhabditis elegans homologues were linked to a lethal RNA interference phenotype. This detailed exploration, combined with future transcriptomic sequencing of all developmental stages of D. viviparus, will facilitate future investigations of the molecular biology of this parasitic nematode as well as genomic sequencing. These advances will underpin the discovery of new drug and/or vaccine targets, focused on biotechnological outcomes.
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[
Autophagy,
2007]
Autophagy is a catabolic process in which long-lived proteins and organelles are degraded for recycling in the cytoplasm. In the nematode Caenorhabditis elegans autophagy is associated with formation of the dauer larva, an alternative developmental stage that worms can enter under poor growth conditions. We have shown that C. elegans mutants that experience caloric restriction because they are feeding-defective also exhibit elevated autophagy and decreased levels of fat deposits, as well as smaller cells and, consequently, a smaller body size. Our results suggest novel relationships between caloric restriction, longevity, body size and autophagy.
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[
Bioessays,
1993]
The dauer larva is a specialized third-larval stage of Caenorhabditis elegans that is long-lived and resistant to environmental insult. The dauer larva is formed in response to a high external concentration of a constitutively secreted pheromone. Response to the dauer-inducing pheromone of C. elegans is a promising genetic model for metazoan chemosensory transduction. More than 20 genes have been identified that are required for normal pheromone response. The functions of these genes include production of the pheromone, exposure of sensory neuron endings to the environment, structural and functional integrity of those sensory endings, and the capacity of sensory neurons to make appropriate output. Genetic evidence suggests that two partially redundant sensory pathways act in concert to control dauer formation. At least two classes of chemosensory neurons, ADF and ASI, are implicated in the pheromone response. On the basis of on these findings, a speculative model for the pheromone response is proposed. In this model, the neurons ADF and ASI are pheromone sensors that repress dauer formation in the absence of pheromone and derepress dauer formation in response to pheromone. It is currently unclear whether or not the two genetically defined sensory pathways both act in ADF and ASI.
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[
Methods Cell Biol,
2011]
The dauer state is a non-feeding, alternative L3 state characterized by a number of distinctive metabolic and morphological changes. There are many naturally occurring dauer-inducing pheromones, termed daumones, that have been suggested by some to exhibit differences in dauer-inducing activity. Here, we have established a standard dauer-formation assay that uses synthetic daumones 1, 2, and 3, the three major daumones. To analyze the proteome of Caenorhabditis elegans in the dauer state, we focused on O-GlcNAc modification, a cytosolic modification of proteins that is known to interact either competitively or synergistically with protein phosphorylation. Protein O-GlcNAc modification is an important biological process in cells that can ensure the timely response to extracellular stimuli, such as daumone, and maintain cellular homeostasis. Establishing a standard method for assaying dauer formation using different synthetic daumones, and using differences in O-GlcNAcylated proteins during the dauer state to analyze the dauer proteome will lead to a better understanding of dauer biology of C. elegans in the context of animal longevity and adaptation under harsh environments.
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[
Curr Top Dev Biol,
2008]
We review mechanistic and evolutionary aspects of interactions between the model organism Caenorhabditis elegans and its environment. In particular, we focus on environmental effects affecting developmental mechanisms. We describe natural and laboratory environments of C. elegans and provide an overview of the different environmental responses of this organism. We then show how two developmental processes respond to changes in the environment. First, we discuss the development of alternative juvenile stages, the dauer and non-dauer larva. This example illustrates how development responds to variation in the environment to generate complex phenotypic variation. Second, we discuss the development of the C. elegans vulva. This example illustrates how development responds to variation in the environment while generating an invariant final phenotype.