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International journal for parasitology [journal]
- Hc-fau, a novel gene regulating diapause in the nematode parasite Haemonchus contortus. [JOURNAL ARTICLE]
- Int J Parasitol 2014 Jul 21.
Diapause induced in the early fourth stage of Haemonchus contortus is a strategy to adapt this nematode to hostile environmental conditions. In this study, we identified a new gene, Hc-fau, a homologue of human fau and Caenorhabditis elegans Ce-rps30. Hc-fau encodes two proteins through alternative RNA splicing, Hc-FAUA and Hc-FAUB, consisting of 130 and 107 amino acids, respectively. Hc-FAU possesses a diverged ubiquitin-like (UBiL) protein domain and a conserved ribosome protein S30 domain. The protein is ubiquitously expressed, except in the gonad. However Hc-fau transcripts decrease significantly in diapausing L4s of H. contortus. In C. elegans, knockdown of Ce-rps30 confers an extended lifespan, increased lipid storage in the intestine and shortened body length. These morphological characteristics are comparable with dauer larvae of C. elegans, in which the gonad is condensed considerably. In contrast, a shortened lifespan is observed in C. elegans over-expressing Hc-faua, and especially Hc-faub, with hatching failure detected. The genes of insulin/IGF-1 signaling (IIS), TGF-β, cGMP, dafachronic acid (DA), apoptosis (AP) and fatty acids (FA) metabolism are all down-regulated in Ce-rps30RNAi (RNA interference) worms, except for akt-1 and daf-16. However, daf-16 up-regulation is inconsistent with its target gene down-regulation and the result from a heat stress assay in these worms. Daf-16 RNAi conducted in Ce-rps30 (tm6034/nt1) mutants failed to rescue the worms. The S30 domain stays in the nucleus, while UBiL accumulates in the cytoplasm. Compared with Hc-FAUA, results of UBiL domain and S30 domain over-expression indicate synergism between UBiL and S30 in regulating lifespan and reproduction. These results suggest the potential functions of Hc-fau in regulating larval diapause in Haemonchus contortus.
- Neuropeptidergic control of the hindgut in the black-legged tick Ixodes scapularis. [JOURNAL ARTICLE]
- Int J Parasitol 2014 Jul 21.
The hindgut, as a part of the tick excretory system, plays an important physiological role in maintaining homeostasis and waste elimination. Immunoreactive projections from the synganglion to the hindgut were found using antibodies against four different neuropeptides: FGLamide related allatostatin (FGLa/AST), myoinhibitory peptide (MIP), SIFamide, and orcokinin. The presence of FGLa/AST, MIP and SIFamide in both synganglia (source) and hindgut (target organ) extracts was confirmed by MALDI-TOF. Tissue-specific PCR revealed the expression of four putative FGLa/AST receptors and an SIFamide receptor (SIFa-R) in the hindgut. An antibody against Ixodes scapularis SIFa-R detected immunoreactive spots in epithelial cells as well as the visceral muscles surrounding the rectal sac, while staining with the antibody against MIP receptor 1 (MIP-R1) revealed that the immunoreactivity was only associated with the visceral muscles. In hindgut motility assays, SIFamide activated hindgut motility in a dose-dependent manner. None of other three neuropeptides (FGLa/AST, MIP and orcokinin) activated hindgut motility when tested alone. MIP antagonized the SIFamide-stimulated hindgut mobility when it was tested in combination with SIFamide.
- Genetic structure in a progenetic trematode: signs of cryptic species with contrasting reproductive strategies. [JOURNAL ARTICLE]
- Int J Parasitol 2014 Jul 21.
Complexes of cryptic species are rapidly being discovered in many parasite taxa, including trematodes. However, after they are found, cryptic species are rarely distinguished from each other with respect to key ecological or life history traits. In this study, we applied an integrative taxonomic approach to the discovery of cryptic species within Stegodexamene anguillae, a facultatively progenetic trematode common throughout New Zealand. The presence of cryptic species was determined by the genetic divergence found in the mitochondrial cytochrome c oxidase I (COI) gene, the 16S rRNA gene and the nuclear 28S gene, warranting recognition of two distinct species and indicating a possible third species. Speciation was not associated with geographic distribution or microhabitat within the second intermediate host; however frequency of the progenetic reproductive strategy (and the truncated life cycle associated with it) was significantly greater in one of the lineages. Therefore, two lines of evidence, molecular and ecological, support the distinction between these two species and suggest scenarios for their divergence.
- Enzymology of the nematode cuticle: A potential drug target? [Journal Article, Review]
- Int J Parasitol Drugs Drug Resist 2014 Aug; 4(2):133-41.
All nematodes possess an external structure known as the cuticle, which is crucial for their development and survival. This structure is composed primarily of collagen, which is secreted from the underlying hypodermal cells. Extensive studies using the free-living nematode Caenorhabditis elegans demonstrate that formation of the cuticle requires the activity of an extensive range of enzymes. Enzymes are required both pre-secretion, for synthesis of component proteins such as collagen, and post-secretion, for removal of the previous developmental stage cuticle, in a process known as moulting or exsheathment. The excretion/secretion products of numerous parasitic nematodes contain metallo-, serine and cysteine proteases, and these proteases are conserved across the nematode phylum and many are involved in the moulting/exsheathment process. This review highlights the enzymes required for cuticle formation, with a focus on the post-secretion moulting events. Where orthologues of the C. elegans enzymes have been identified in parasitic nematodes these may represent novel candidate targets for future drug/vaccine development.
- Quantitative proteomic analysis of amphotericin B resistance in Leishmania infantum. [Journal Article]
- Int J Parasitol Drugs Drug Resist 2014 Aug; 4(2):126-32.
Amphotericin B (AmB) in its liposomal form is now considered as either first- or second-line treatment against Leishmania infections in different part of the world. Few cases of AmB resistance have been reported and resistance mechanisms toward AmB are still poorly understood. This paper reports a large-scale comparative proteomic study in the context of AmB resistance. Quantitative proteomics using stable isotope labeling of amino acids in cell culture (SILAC) was used to better characterize cytoplasmic and membrane-enriched (ME) proteomes of the in vitro generated Leishmania infantum AmB resistant mutant AmB1000.1. In total, 97 individual proteins were found as differentially expressed between the mutant and its parental sensitive strain (WT). More than half of these proteins were either metabolic enzymes or involved in transcription or translation processes. Key energetic pathways such as glycolysis and TCA cycle were up-regulated in the mutant. Interestingly, many proteins involved in reactive oxygen species (ROS) scavenging and heat-shock proteins were also up-regulated in the resistant mutant. This work provides a basis for further investigations to understand the roles of proteins differentially expressed in relation with AmB resistance.
- Idiosyncratic quinoline central nervous system toxicity: Historical insights into the chronic neurological sequelae of mefloquine. [Journal Article]
- Int J Parasitol Drugs Drug Resist 2014 Aug; 4(2):118-25.
Mefloquine is a quinoline derivative antimalarial which demonstrates promise for the treatment of schistosomiasis. Traditionally employed in prophylaxis and treatment of chloroquine-resistant Plasmodium falciparum malaria, recent changes to the approved European and U.S. product labeling for mefloquine now warn of a risk of permanent and irreversible neurological sequelae including vertigo, loss of balance and symptoms of polyneuropathy. The newly described permanent nature of certain of these neurological effects challenges the conventional belief that they are due merely to the long half-life of mefloquine and its continued presence in the body, and raises new considerations for the rational use of the drug against parasitic disease. In this opinion, it is proposed that many of the reported lasting adverse neurological effects of mefloquine are consistent with the chronic sequelae of a well characterized but idiosyncratic central nervous system (CNS) toxicity syndrome (or toxidrome) common to certain historical antimalarial and antiparasitic quinolines and associated with a risk of permanent neuronal degeneration within specific CNS regions including the brainstem. Issues in the development and licensing of mefloquine are then considered in the context of historical awareness of the idiosyncratic CNS toxicity of related quinoline drugs. It is anticipated that the information presented in this opinion will aid in the future clinical recognition of the mefloquine toxidrome and its chronic sequelae, and in informing improved regulatory evaluation of mefloquine and related quinoline drugs as they are explored for expanded antiparasitic use and for other indications.
- Uptake of benzimidazoles by Trichuris suis in vivo in pigs. [Journal Article]
- Int J Parasitol Drugs Drug Resist 2014 Aug; 4(2):112-7.
It is recognized that the clinical efficacy of single dose benzimidazoles (BZs) against the nematode, Trichuris suis of pigs and the closely related Trichuris trichiura in humans is only poor to moderate. Recent in vitro studies have indicated that a low uptake of fenbendazole (FBZ) in T. suis may be responsible for its poor efficacy. The aim of this study was to investigate this hypothesis by measuring the concentrations of FBZ and its metabolites, oxfendazole (OXF) and FBZ sulphone (FBZSO2), in T. suis isolated from FBZ treated pigs and in plasma of the pigs. The highest concentration of FBZ measured in T. suis was 66.6 pmol/mg dry worm tissue which was approximately half of what was measured in a previous in vitro study. The correlation between drug concentrations in plasma and in T. suis worms was highly positive for OXF (r = 0.93, P = 0.0007) and FBZSO2 (r = 0.85, P = 0.007), but no correlation was found for FBZ. This study shows that the low uptake of FBZ observed for T. suis in vitro, also takes place in vivo. The high and significant correlations between OXF and FBZSO2 concentrations in plasma of the pigs and T. suis (and the lack of this correlation for FBZ) suggests that the metabolites reach the worms via the blood-enterocyte interface while FBZ primarily reaches the worms via the intestinal lumen of the host.
- Drug repurposing and human parasitic protozoan diseases. [Journal Article, Review]
- Int J Parasitol Drugs Drug Resist 2014 Aug; 4(2):95-111.
Parasitic diseases have an enormous health, social and economic impact and are a particular problem in tropical regions of the world. Diseases caused by protozoa and helminths, such as malaria and schistosomiasis, are the cause of most parasite related morbidity and mortality, with an estimated 1.1 million combined deaths annually. The global burden of these diseases is exacerbated by the lack of licensed vaccines, making safe and effective drugs vital to their prevention and treatment. Unfortunately, where drugs are available, their usefulness is being increasingly threatened by parasite drug resistance. The need for new drugs drives antiparasitic drug discovery research globally and requires a range of innovative strategies to ensure a sustainable pipeline of lead compounds. In this review we discuss one of these approaches, drug repurposing or repositioning, with a focus on major human parasitic protozoan diseases such as malaria, trypanosomiasis, toxoplasmosis, cryptosporidiosis and leishmaniasis.
- microRNAs of parasitic helminths - Identification, characterization and potential as drug targets. [Journal Article, Review]
- Int J Parasitol Drugs Drug Resist 2014 Aug; 4(2):85-94.
microRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation. They were first identified in the free-living nematode Caenorhabditis elegans, where the miRNAs lin-4 and let-7 were shown to be essential for regulating correct developmental progression. The sequence of let-7 was subsequently found to be conserved in higher organisms and changes in expression of let-7, as well as other miRNAs, are associated with certain cancers, indicating important regulatory roles. Some miRNAs have been shown to have essential functions, but the roles of many are currently unknown. With the increasing availability of genome sequence data, miRNAs have now been identified from a number of parasitic helminths, by deep sequencing of small RNA libraries and bioinformatic approaches. While some miRNAs are widely conserved in a range of organisms, others are helminth-specific and many are novel to each species. Here we review the potential roles of miRNAs in regulating helminth development, in interacting with the host environment and in development of drug resistance. Use of fluorescently-labeled small RNAs demonstrates uptake by parasites, at least in vitro. Therefore delivery of miRNA inhibitors or mimics has potential to alter miRNA activity, providing a useful tool for probing the roles of miRNAs and suggesting novel routes to therapeutics for parasite control.
- Drug-efflux and target-site gene expression patterns in Haemonchus contortus larvae able to survive increasing concentrations of levamisole in vitro. [Journal Article]
- Int J Parasitol Drugs Drug Resist 2014 Aug; 4(2):77-84.
While there is some evidence that changes in nicotinic acetylcholine receptor (nAChR) subunits confer resistance to levamisole in gastrointestinal helminth parasites, the exact nature of the resistance mechanism(s) is unclear. We utilised the presence of a resistant fraction within the Wallangra 2003 isolate of Haemonchus contortus larvae in order to subdivide the population into three subpopulations of larvae able to survive increasing concentrations of the drug. We then measured gene expression levels in the subpopulations and the larval population as a whole, focusing on genes encoding the subunit components of levamisole-sensitive receptors, genes encoding ancillary proteins involved in receptor assembly, and P-glycoprotein (P-gp) genes. The subpopulation surviving the lowest levamisole concentration showed increases of 1.5- to 3-fold in a number of P-gp genes (Hco-pgp-3, -4, -10, and -14) alongside unchanged receptor genes, compared to the whole Wallangra larval population. On the other hand, the subpopulation surviving the intermediate levamisole concentration showed an increase in only a single P-gp (Hco-pgp-14), alongside decreases in some receptor subunit (Hco-unc-63a) and ancillary protein genes (Hco-unc-50, Hco-ric-3.1 and 3.1). The subpopulation surviving the highest levamisole concentration showed further decreases in receptor subunit genes (Hco-unc-63a and Hco-unc-29 paralogs) as well as genes involved in receptor assembly (Hco-unc-74, Hco-unc-50, Hco-ric-3.1 and 3.1), alongside no increased P-gp gene levels. This suggests a biphasic pattern of drug resistance in the larvae of this worm isolate, in which a non-specific P-gp-mediated mechanism confers low levels of resistance, while higher level resistance is due to altered receptor subunit composition as a result of changes in both subunit composition and in the levels of proteins involved in receptor assembly.