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| Genetics/genomics |
| Title: | Long PCR-based amplification of the entire mitochondrial genome from single parasitic nematodes |
| Authors: | Hu, M Chilton, NB Gasser, RB |
| Journal: | Mol. Cell. Probes (2002) 16(4):261-267 |
| Abstract: + | Mitochondrial genome sequences provide useful markers for investigating population genetic structures because of their maternal inheritance and high evolutionary rates. There is, however, a paucity of information on mitochondrial genomes for many parasitic organisms, including nematodes, which appears to relate mainly to technical limitations and (for modestly funded laboratories) the cost associated with full mitochondrial genome sequencing. In this article, we describe a simple, relatively inexpensive long-PCR approach for the amplification (using two sets of primers) of the entire mitochondrial genome from individual parasitic nematodes for subsequent sequencing, which overcomes these limitations. We employed two species of human hookworm (Ancylostoma duodenale and Necator americanus; order Strongylida) to establish the long-PCR conditions, and then extended its use to a number of other species of parasitic nematode of the class Secernentea (orders Strongylida, Ascaridida and Rhabditida). The long-PCR method for the amplification of the entire mitochondrial genome from single nematodes, coupled with direct sequencing of amplicons, provides a useful tool for the comparative analysis of genome organisation and evolution of a range of nematode groups. It also creates a platform for molecular ecological and population genetic studies. (C) 2002 Elsevier Science Ltd. All rights reserved. |
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| Title: | The mitochondrial genomes of the human hookworms, Ancylostoma duodenale and Necator americanus (Nematoda : Secernentea) |
| Authors: | Hu, M Chilton, NB Gasser, RB |
| Journal: | Int. J. Parasit. (2002) 32(2):145-158 |
| Abstract: + | The complete mitochondrial genome sequences were determined for two species of human hookworms, Ancylostoma duodenale ( 13,721 bp) and Necator americanus (13,604 bp). The circular hookworm genomes are amongst the smallest reported to date for any metazoan organism. Their relatively small size relates mainly to a reduced length in the AT-rich region. Both hookworm genomes encode 12 protein. two ribosomal RNA and 22 transfer RNA genes, but lack the ATP synthetase subunit 8 gene, which is consistent with three other species of Secernentea studied to date. All genes are transcribed in the same direction and have a nucleotide composition high in A and T, but low in G and C. The AT bias had a significant effect on both the codon usage pattern and amino acid composition of proteins. For both hookworm species. genes were arranged in the same order as for Caenorhabditis elegans, except for the presence of a non-coding region between genes nad3 and nad5. In A. duodenale, this non- coding region is predicted to form a stem-and-loop structure which is not present in N. americanus. The mitochondrial genome structure for both hookworms differs from Ascaris suum only in the location of the AT-rich region, whereas there are substantial differences when compared with Onchocerca volvulus, including four gene or gene-block translocations and the positions of some transfer RNA genes and the AT-rich region. Based on genome organisation and amino acid sequence identity, A. duodenale and N. americanus were more closely related to C. elegans than to A. suum or O. volvulus (all secernentean nematodes), consistent with a previous phylogenetic study using ribosomal DNA sequence data. Determination of the complete mitochondrial genome sequences for two human hookworms (the first members of the order Strongylida ever sequenced) provides a foundation for studying the systematics. population genetics and ecology of these and other nematodes of socio-economic importance. (C) 2002 Australian Society for Parasitology Inc. Published by Elsevier Science Ltd. All rights reserved. |
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| Title: | The rusty genotypes |
| Authors: | Cadet, E Warin, R Perez, AS Rochette, J Capron, D |
| Journal: | M S-Med. Sci. (2001) 17(6-7):753-759 |
| Abstract: + | Two main genetic entities lead to iron overload: hemochromatosis and thalassemia. Genetic hemochromatosis HFE-1 type is a common autosomal recessive disease affecting about 1/300 individuals of european descent. HFE-1 type hemochromatosis is associated with the C282Y mutation of the HFE gene, and the H63D mutation to a much lesser degree. Allele frequency of the C282Y type is about 6,6 % in Europe and the average of the H63D allele frequency is about 13,4 %. Thalassemia is prevalent in a wide belt of countries extending from the mediterranean basin down to Africa and through the Middle East, the indian subcontinent and into south east Asia and China. Population genetic studies show that thalassemias are common where primary hemochromatosis is not. There is little reproductive disavantage to C282Y homozygotes and even less to heterozygotes. No major disvantage appears for the H63D mutation. Our results suggest that there is or has been selection pressure favoring these mutations making genetic drift an unlikely explanation. Until now it has been assumed that the selective advantage conferred by HFE mutations was the prevention of iron deficiency; this would include protection against anemia due to hookworm infestation, multiples pregnancies, a diet lacking in iron or any combination of these factors. However if this were solely the case, then one might expect that one more of the HFE mutations would have reached fixation in countries where there are high levels of anemia; this has not been observed yet. Because of wild-type HFE protein is expressed at the cell surface, one could speculate that this protein is the receptor for some infectious agents. The region of the protein that might be involved could be the exon 3 which encodes the alpha 1 domain where the H63D mutation is found. The C282Y mutation does not allow the HFE-1 protein to reach the cell surface. Like thalassemia, hemochromatosis could be the result of a selection pressure involving resistance to infectious agent. By now, the entire world population carries an unfortunate genetic burden leading to iron overload. |
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| Title: | Immune evasion genes from filarial nematodes |
| Authors: | Maizels, RM Gomez-Escobar, N Gregory, WF Murray, J Zang, XX |
| Journal: | Int. J. Parasit. (2001) 31(9):889-898 |
| Abstract: + | Helminth parasites have large genomes (similar to 10(8) bp) which art: likely to encode a spectrum of products able to block or divert the host immune response. We have employed three parallel approaches to identify the first generation of 'immune evasion genes from parasites such as the filarial nematode Brugia malayi. The first strategy is a conventional route to characterise prominent surface or secreted antigens. In this way we have identified a 15-kDa protein. which is located on the surface of both L3 and adult B. malayi, and secreted by these parasites in vitro as a member of the cystatin (cysteine protease inhibitor) family. This product, Bm-CPI-2, blocks conventional cysteine proteases such as papain, but also the aspariginyl endopeptidase involved in the Class II antigen processing pathway in human B cells. In parallel, we identified the major T cell-stimulating antigen from the microfilarial stage as a serpin (serine protease: inhibitor), Bm-SPN-2. Microfilariae secrete this product which blocks two key proteases of the neutrophil, a key mediator of inflammation and innate immunity. The second route involves a priori hypotheses that helminth parasites encode homologues of mammalian cytokines such as TGF-P which are members of broad, ancient metazoan gene families. We have identified two TGF-beta homologues in B. malayi, and shown that one form (Bm-TGH-2) is both secreted by adult parasites in vitro and able to bind to host TGF-beta receptors. Likewise, B. malayi expresses homologues of mammalian MIF. which are remarkably similar in both structure and function to the host protein, even though amino acid identity is only 28%. Finally. we deployed a third method of selecting critical genes, using an expression-based criterion to select abundant mRNAs taken from key points in parasite life histories. By this means, we have shown that the major transcript present in mosquito-borne infective larvae, Bm-ALT, is a credible vaccine candidate for use against lymphatic filariasis. while a second abundantly-expressed gene. Bm-VAL-1, is similar to a likely vaccine antigen being developed against hookworm parasites. (C) 2001 Australian Society for Parasitology Inc. published by Elsevier Science Ltd. All rights reserved. |
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| Title: | Proteinases and associated genes of parasitic helminths |
| Authors: | Tort, J Brindley, PJ Knox, D Wolfe, KH Dalton, JP |
| Journal: | Adv.Parasitol. (1999) 43:161-266 |
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| Title: | Genes and genomes of Necator americanus and related hookworms |
| Authors: | Blaxter, M |
| Journal: | Int. J. Parasit. (2000) 30(4):347-355 |
| Abstract: + | The human hookworms (Necator americanus and Ancylostoma duodenale) infect over one billion people. The phylogenetic relationships of the human hookworms suggest independent acquisition of the human host. The hookworms probably have a haploid chromosome number n = 6. and an XX-XO sex determination mechanism is likely to be used. Genetic and molecular research on hookworms is in its infancy, but several important genes and gene products have already been identified. Of note are cathepsin genes, a family of secreted proteins known as Ancylostoma activation-associated proteins and a family of anticoagulants. The inception of an expressed sequence tag program on the human hookworm, N. americanus, promises to yield many new genes with novel functions in the biology of these important parasites. (C) 2000 Australian Society for Parasitology Inc. Published by Elsevier Science. All rights reserved. |
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| Title: | A survey of genes expressed in adults of the human hookworm, Necator americanus |
| Authors: | Daub, J Loukas, A Pritchard, DI Blaxter, M |
| Journal: | Parasitology (2000) 120:171-184 |
| Abstract: + | Hookworms are gut-dwelling, blood-feeding nematodes that infect hundreds of millions of people, particularly in the tropics. As part of a program aiming to define novel drug targets and vaccine candidates for human parasitic nematodes, genes expressed in adults of the human hookworm Necator americanus were surveyed by the expressed sequence tag approach. In total 161 new hookworm genes were identified. For the majority of these, a function could be assigned by homology. The dataset includes proteases, protease inhibitors, a lipid binding protein, C-type lectins, an anti-bacterial factor, globins and other genes of interest from a drug or vaccine development viewpoint. Three different classes of small, secreted proteins were identified that may be involved in the host-parasite interaction, including potential potassium channel blocking peptides. One third of the genes were novel. These included highly expressed, secreted (glyco)proteins which may be part of the excretory-secretory products of these important pathogens. Of particular interest are a family of 9 genes with similarity to the immunomodulatory protein, neutrophil inhibitory factor, that may play a role in establishing an immunocompromised niche for this successful parasite. |
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| Title: | Sequence differences in the internal transcribed spacers of DNA among four species of hookworm (Ancylostomatoidea : Ancylostoma) |
| Authors: | Chilton, NB Gasser, RB |
| Journal: | Int. J. Parasit. (1999) 29(12):1971-1977 |
| Abstract: + | The two ribosomal DNA internal transcribed spacers (1 and 2) of the hookworms Ancylostoma caninum, A. tubaeforme, A. ceylanicum and A. duodenale were sequenced. The sequence lengths were similar among the four species, except that A. ceylanicum had slightly longer (by 5-7 bp) internal transcribed spacer 1 and 2 sequences. The predicted secondary structure of the internal transcribed spacer 2 precursor rRNA was similar for all species, despite interspecific differences in primary sequence ranging from 0.9% to 13.2%. Interspecific differences in internal transcribed spacer 1 sequence ranged from 0.9% to 7.5%. A cladistic analysis of the sequence data, using the human hookworm Necator americanus as the outgroup, provided little resolution of the phylogenetic relationships, except that A. ceylanicum occurred on a branch external to the other three species. Nonetheless, internal transcribed spacers 1 and 2 may provide useful phylogenetic information at higher taxonomic levels within the superfamily Ancylostomatoidea. (C) 1999 Australian Society for Parasitology Inc. Published by Elsevier Science Ltd. All rights reserved. |
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| Population genetics/sociological issues |
| Title: | Single-strand conformation polymorphism-based analysis of mitochondrial cytochrome c oxidase subunit 1 reveals significant substructuring in hookworm populations |
| Authors: | Hu, M Chilton, NB Zhu, XQ Gasser, RB |
| Journal: | Electrophoresis (2002) 23(1):27-34 |
| Abstract: + | Sequence heterogeneity in a portion of the mitochondrial cytochrome c oxidase subunit 1 gene (pcox1) was measured for the hookworms, Ancylostoma caninium from Australia, A. duodenale! from China, and Necator americanus from China and Togo using single-strand conformation polymorphism (SSCP) analysis combined with DNA sequencing. The pcox1 sequences were characterised for individual nematodes displaying genetic variation within each of the three species, and those were compared with pcox1 sequences of four other species of hookworm. While intraspecific variation in the pcox1 sequence ranged from 0.5 to 8.6% for A. caninum, 0.3 to 3.3% for A. duodenale, and 0.3 to 4.3% for N. americanus, interspecific differences varied from 4.8 to 12.9%. Sequence data also provided information on nucleotide compositions and substitution patterns. Genetically distinct groups were detected within A. caninum and A. duodenale, indicating significant population substructuring within these species. Also, N. americanus individuals from China all differed from those from Togo at four nucleotide positions, supporting a previous proposal (based on ribosomal DNA sequence data) that N. americanus may represent a species complex. The findings indicated the value of pcox1 sequence data and the mutation scanning approach for studying the genetic structures of hookworm populations, which should have important epidemiological relevance. |
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| Title: | A study of risk factors for intestinal helminth infections using epidemiological and anthropological approaches |
| Authors: | Olsen, A Samuelsen, H Onyango-Ouma, W |
| Journal: | J. Biosoc. Sci. (2001) 33(4):569-584 |
| Abstract: + | This study, conducted in Kisumu District, Kenya, identified important risk factors for infection with intestinal helminths using traditional epidemiological methods. This was combined with a rapid assessment study using qualitative methods, which focused on sanitation practices and local illness perceptions. The multiple logistic regression analysis revealed that the absence of latrines was a significant predictor for hookworm infection with an odds ratio (OR) of 1.9. The analysis also revealed that households without soap had a 2.6 times higher risk of being infected with Ascaris lumbricoides compared with households where soap was available, and that the number of inhabitants living in a household was a significant predictor for infections with hookworms (OR=3.2). Furthermore, the presence of children of 5 years and under in the household was a predictor for infection with A. lumbricoides (OR=2.7), while the absence of this age group was a predictor for hookworm infection (OR=3.8). The qualitative part of the study revealed that people did not consider worms as a serious health threat, but as a nuisance. Among the population, latrines were seen as beneficial because they were believed to prevent disease, to provide privacy and to keep the environment free of faeces. Handwashing was done many times a day but usually not with soap, which was mainly used when bathing or washing the whole body. Many inhabitants in a household or the presence of children of 5 years and under were never mentioned as being a disadvantage, and these elements would therefore be difficult to include in a control strategy. Since the lack of latrines and of soap were identified as risk factors for infection, while latrines, soap and medicine were seen as assets by the population, it is suggested that helminth control interventions should be concentrated within these areas in this particular society. |
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| Title: | Is Necator americanus approaching a mutualistic symbiotic relationship with humans? |
| Authors: | Pritchard, DI Brown, A |
| Journal: | Trends Parasitol. (2001) 17(4):169-172 |
| Abstract: + | The hookworm Necator americanus establishes infections of impressive longevity in the immunologically hostile environment of its human host. In the process, it promotes pronounced T- helper 2 (Th2) cell activity, which in turn seemingly affords the host at least a degree of protection. Given the relatively asymptomatic nature of infection, we argue here that Necator americanus might be approaching a mutualistic symbiotic relationship with humans. In our view, infection is controlled by the immune system while being supported by a subtle immune- evasion strategy that is tolerated and possibly beneficial to the host in certain immunological circumstances, such as in counterbalancing potentially damaging Th1 responses. |
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| Title: | The future impact of societal and cultural factors on parasitic disease - some emerging issues |
| Authors: | Thompson, RCA |
| Journal: | Int. J. Parasit. (2001) 31(9):949-959 |
| Abstract: + | A variety of societal and cultural factors will increase host exposure or susceptibility to infectious agents. particularly parasites. Such Factors have already had a major impact on the emergence of infectious diseases and the situation is likely; to worsen further as we enter the new millennium. The changes that are enhancing the spread and transmission of parasitic diseases, as well as those which are adversely affecting host responsiveness, are examined with reference to specific parasites. (C) 2001 Australian society for Parasitology Inc. Published by Elsevier Science Ltd. All rights reserved. |
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| Title: | Genetic structure of populations of the human hookworm, Necator americanus, in China |
| Authors: | Hawdon, JM Li, T Zhan, B Blouin, MS |
| Journal: | Mol. Ecol. (2001) 10(6):1433-1437 |
| Abstract: + | Twenty-one to 58 individual Necator americanus were sampled from each of four villages in south-western China. Each nematode was sequenced for 588 bp of the mitochondrial cytochrome oxidase I gene. Allelic and nucleotide diversity varied two-fold among villages. Overall Fs, among populations was approximate to 0.28, but this large value resulted from one low-diversity population that had a large genetic distance to the other three populations (F-ST = 0.10 without that population). There was no correlation between geographical and genetic distance among sites. Thus, the genetic structure of this species in China may be characterized by variable effective sizes and uneven movement among sites. We discuss the implications of this genetic structure for vaccine development and the spread of drug resistance in human hookworms, and compare the genetic structure of hookworms with that of other nematodes. |
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| Title: | The public health importance of hookworm disease |
| Authors: | Crompton, DWT |
| Journal: | Parasitology (2000) 121:S39-S50 |
| Abstract: + | The public health significance of hookworm disease is briefly reviewed. The latest evidence confirms that blood loss caused by the worms' feeding activity in the gut is a contributing factor in the development of poor iron status leading to iron- deficiency anaemia. The World Health Organization has identified adolescent girls and women of child-bearing age as high-risk groups regarding the impact of hookworm disease. The merits of treating pregnant women with anthelminthic drugs after the first trimester are discussed. |
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| Title: | A mutation scanning approach for the identification of hookworm species and analysis of population variation |
| Authors: | Gasser, RB Monti, JR Bao-Zhen, QA Polderman, AM Nansen, P Chilton, NB |
| Journal: | Mol. Biochem. Parasitol. (1998) 92(2):303-312 |
| Abstract: + | To overcome limitations in the morphological identification of different developmental stages of hookworms to species, we have established a polymerase chain reaction-linked single strand conformation polymorphism technique (PCR-SSCP) utilizing the internal transcribed spacers (ITS) of ribosomal (r)DNA. These spacers were specifically chosen because they provide reliable species markers for strongylid nematodes. ITS spacers were amplified by PCR from DNA derived from individual parasites of seven species of hookworm, then denatured and subjected to electrophoresis in a mutation detection enhancement (MDE) (non- denaturing) gel matrix. PCR-SSCP analysis showed that the single-strand ITS patterns produced allowed the unequivocal identification of all species. The method also allowed the direct display of sequence variation within some species where multiple individual worms were examined. These findings demonstrate the usefulness of the SSCP approach for hookworm identification, the detection of population variation and the direct display of sequence variation in rDNA. (C) 1998 Elsevier Science B.V. All rights reserved. |
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| Title: | Transmission patterns and the epidemiology of hookworm infection |
| Authors: | Chan, MS Bradley, M Bundy, DAP |
| Journal: | Int. J. Epidemiol. (1997) 26(6):1392-1400 |
| Abstract: + | Background. This paper presents a suite of models of hookworm transmission dynamics which vary the mixing patterns and rates of contamination and infection between children and adults. In this context mixing refers to the degree of epidemiological communication between children and adults, for example, whether adults are likely to get infected from infective material passed by children. Methods. Three models are described which represent random mixing, no mixing and restricted mixing respectively. Child, adult and population targeted chemotherapy programmes are examined and compared between these models. Data from a hookworm control programme in Zimbabwe were analysed with respect to their fit to the various models. Results. The analysis suggests that some mixing does occur and that in this study location, the sites where adults deposit faeces are more likely to lead to subsequent contamination than the sites children use. Conclusions. Mixing patterns may have a profound effect on transmission dynamics and should be considered in relation to design of control programmes. |
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| Immunity/immune responses |
| Title: | Successful vaccination of BALB/c mice against human hookworm (Necator americanus): the immunological phenotype of the protective response |
| Authors: | Girod, N Brown, A Pritchard, DI Billett, EE |
| Journal: | Int. J. Parasit. (2003) 33(1):71-80 |
| Abstract: + | In this murine (BALB/c) model of necatoriasis, high levels of protection against challenge infection by Necator americanus larvae (n = 300) were afforded by successive vaccinations at 14-day intervals, either subcutaneously or percutaneously, with gamma-irradiated N. americanus larvae (n = 300). Percutaneous vaccination was significantly more effective than the subcutaneous route, with pulmonary larval burdens at 3 days post-infection being reduced by 97.8 vs. 89.3%, respectively, after three immunisations (P < 0.05). No worms were recovered from the intestines of thrice vaccinated mice. Two percutaneous vaccinations also reduced worm burdens, by 57% in the lungs and 98% in the intestines; P < 0.05. In vaccinated animals, lung pathology (mainly haemorrhage) following infection was greatly reduced compared with non-vaccinated animals. In vaccinated mice (but not in non-vaccinated mice) mast cells accumulated in the skin and were degranulated. RT-PCR analyses of mRNAs in the skin of vaccinated animals indicated increased expression of interleukin (IL)-4 relative to gamma-interferon (gamma-IFN). Lymphocytes from the axillary (skin-draining) lymph nodes of vaccinated mice, stimulated in vitro with concanavalin A, exhibited enhanced secretion of IL-4 protein and a higher IL- 4/gamma-IFN protein ratio than lymphocytes from non-vaccinated animals. In vaccinated mice, levels of IgG1 and IgG3 (directed against larval excretory/secretory products) were elevated for the most part compared with those in non-vaccinated animals. These data demonstrate the successful vaccination of BALB/c mice against human hookworm infection and suggest that a localised Th2 response may be important for conferring protection against necatoriasis. (C) 2002 Australian Society for Parasitology Inc. Published by Elsevier Science Ltd. All rights reserved. |
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| Title: | Anthelmintic resistance in human helminths: a review |
| Authors: | Geerts, S Gryseels, B |
| Journal: | Trop. Med. Int. Health (2001) 6(11):915-921 |
| Abstract: + | We briefly review reports on drug resistance in human helminths and compare the factors which contribute to the development of anthelmintic resistance in livestock and man, i.e. high treatment frequency, single-drug regimens, targeting and timing of mass treatments and underdosing. Conclusions are drawn from the mistakes in the treatment and control of livestock helminths. The advantages and inconveniences of current methods for the detection of drug resistance in helminths of livestock are discussed and some suggestions are put forward to standardize the tests for the detection of resistance in human helminths. Finally, based on veterinary experience, some recommendations are made to reduce the risks of development of drug resistance in human helminths. The dramatic and rapid spread of resistance to all major classes of veterinary anthelmintics should be a warning against too strong a reliance on drugs in helminth control programmes. |
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| Title: | Drug-based helminth control in Western Pacific countries: a general perspective |
| Authors: | Urbani, C Palmer, K |
| Journal: | Trop. Med. Int. Health (2001) 6(11):935-944 |
| Abstract: + | Helminthiases still have a relevant detrimental role in the health of large groups of human population. Where poor hygiene and lack of access to education, health services and essential care characterize living conditions, parasitic infections dramatically affect essential aspects of individual life, such as nutrition, cognitive performance, susceptibility to infections and micronutrient deficiency. Severe illness is associated with schistosomiasis, lymphatic filariasis and food- borne trematode infections. Drugs are the cornerstone of control strategies for such infections, the World Health Organization (WHO) list of essential drugs contains several highly efficacious anthelmintics which are all safe, single- dose and cheap. If given regularly to infected communities, these drugs effectively control the morbidity related to the major endemic helminth infections. New strategies for mass drug administration to human populations have been tested, and several endemic Western Pacific countries have achieved excellent results in reducing morbidity in spite of continuous transmission. In this region, experience over the last decades proves the feasibility of helminth control, but also shows the need for long-term commitment and continuous support. |
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| Title: | Immune responses in hookworm infections |
| Authors: | Loukas, A Prociv, P |
| Journal: | Clin. Microbiol. Rev. (2001) 14(4):689-703 |
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| Title: | Parasite-specific antibody and cellular immune responses in humans infected with Necator americanus and Oesophagostomum bifurcum |
| Authors: | Pit, DSS Polderman, AM Baeta, S Schulz-Key, H Soboslay, PT |
| Journal: | Parasitol. Res. (2001) 87(9):722-729 |
| Abstract: + | In this study parasite-specific antibody, cellular reactivity and Th1-type or Th2-type cytokine responses were investigated in humans concurrently infected with Necator americanus and Oesophagostomum bifurcum. The prospects for O. bifurcum- specific serodiagnosis based on IgG4 and IgE were evaluated. IgG4 showed low specificity for O. bifurcum due to antigen cross-reactivity with N. americanus, while IgE specifically distinguished between hookworm and O. bifurcum, and, in doubly infected patients, levels of O. bifurcum-specific as well as N. americanus-specific IgE were significantly elevated compared to those with N. americanus mono-infections. Cellular immunity was not strictly dominated by a Th1- or Th2- type reactivity. In co-infected patients cellular unresponsiveness to parasite antigens was observed, while cellular production of tumour necrosis factor alpha (TNF-alpha) and gamma-interferon (IFN- gamma) was greater in those doubly infected. Th2-type cytokines (interleukin-5 and interleukin-10) were produced in equal amounts by peripheral blood mononuclear cells from individuals with mono- and coinfections. Such mixed Th1-type and Th2-type immune responsiveness associated with persisting gastrointestinal parasitic nematodes may reflect a state of infection at which parasite-induced inflammatory and enteropathogenic responses co-exist, and furthermore, helminth coinfection will not only suppress parasite-specific cellular responsiveness but may also direct cytokine production towards a "permissive Th1-type cytokine profile" that favours parasite persistence. |
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| Title: | Predisposition to hookworm infection in Papua New Guinea |
| Authors: | Quinnell, RJ Griffin, J Nowell, MA Raiko, A Pritchard, DI |
| Journal: | Trans. Roy. Soc. Trop. Med. Hyg. (2001) 95(2):139-+ |
| Abstract: + | Reinfection with hookworm (Necator americanus) following chemotherapy was studied over 8 years in a rural village in Madang Province, Papua New Guinea. Faecal egg counts were performed on up to 202 individuals in July 1988, August: 1990 and November 1996; the study population was treated after sampling in 198 8 and 1990. Reinfection burdens in 1996 did not differ significantly from pretreatment burdens (in 1988), and were significantly higher than burdens in 1990. However, the prevalence of hookworm infection was significantly lower in 1996 than in either 1988 or 1990. There was significant predisposition to high or low bookworm burden between 1990 and 1996; this predisposition was stronger in children than adults. However, there was no detectable predisposition between 1988 and 1996 in individuals who had been treated 2 or more times between surveys. The mean weight of adult hookworms in individual hosts was measured in 1988 and 1990 using worms expelled after chemotherapy. There was a significant positive correlation between mean male hookworm weight in the 2 years, suggesting that individual hosts are predisposed to infection with heavy or light hookworms. These data suggest that differences in host susceptibility are involved in generating predisposition, but that longer-term variation in either exposure or susceptibility limits the period over which significant predisposition can be detected. |
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| Title: | The biochemical basis of anthelmintic action and resistance |
| Authors: | Kohler, P |
| Journal: | Int. J. Parasit. (2001) 31(4):336-345 |
| Abstract: + | The most commonly used modern anthelmintics include the benzimidazoles, the nicotinic agonists, praziquantel, triclabendazole and the macrocyclic lactones. These drugs interfere with target sites: that are tither unique to the parasite or differ in their structural features from those of the homologous counterpart present in the vertebrate host. The benzimidazoles exert their effect by binding selectively and with high affinity to the beta -subunit of helminth microtubule protein. The target site of the nicotinic agonists: (e.g. levamisole, tetrahydropyrimidines) is a pharmacologically distinct nicotinic acetylcholine receptor channel in nematodes. The macrocyclic lactones (e.g. ivermectin. moxidectin) act as agonists of a family of invertebrate-specific inhibitory chloride channels that are activated by glutamic acid, The primary mode of action of other important anthelmintics (e.g. praziquantel, triclabendazole) is unknown. Anthelmintic resistance is: wide-spread and a serious threat to effective control of helminth infections, especially in the veterinary area. The biochemical and genetic mechanisms underlying anthelmintic resistance are not well understood, but appear to be complex and vary among different helminth species and even isolates. The major mechanisms helminths use to acquire drug resistance appear to be through receptor loss or decrease of the: target site affinity for the drug. Knowledge on the mechanisms of drug action and resistance may be exploitable for the development of new drugs and may provide information on ways to overcome parasite resistance, respectively. (C) 2001 Australian Society for Parasitology Inc. Published by Elsevier Science Ltd. All rights reserved. |
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| Title: | Lower hookworm incidence, prevalence, and intensity of infection in children with a bacillus Calmette-Guerin vaccination scar |
| Authors: | Barreto, ML Rodrigues, LC Silva, RCR Assis, AMO Reis, MG Santos, CAST Blanton, RE |
| Journal: | J. Infect. Dis. (2000) 182(6):1800-1803 |
| Abstract: + | Bacillus Calmette-Guerin (BCG), the most common vaccine worldwide, has broad effects on the immune system. Hookworm infections are a major source of morbidity. In response to a preliminary report of BCG vaccination protection against nematodes in human immunodeficiency virus-infected adults, data from an ongoing prospective study were analyzed to determine the intensity (eggs per gram of stool), prevalence, and incidence of different helminths in children with and without a BCG vaccination scar. Adjusted prevalence and incidence ratios were estimated by using logistic regression. Children with a BCG vaccination scar were found to have statistically significantly lower hookworm prevalence (41%), incidence (37%), and mean egg counts (39%), after controlling for age, sex, and socioeconomic factors. There was no BCG association with incidence, prevalence, or intensity of infection with Schistosoma mansoni, Ascaris lumbricoides, or Trichuris trichiura. Such protection would have implications for public health and for research on mechanisms behind human immunological responses to hookworm. |
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| Title: | Anthelmintic resistance and the control of worms |
| Authors: | Coles, GC |
| Journal: | J. Med. Microbiol. (1999) 48(4):323-325 |
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| Title: | Parasitic infections. Treatment and developmental therapeutics. 1. Necatoriasis |
| Authors: | St Georgiev, V |
| Journal: | Curr. Pharm. Design (1999) 5(7):545-554 |
| Abstract: + | Necator americanus is a nematode hookworm of the family Ancylostomatidae, subfamily Necatorinae. This nematode parasite, which is distinguished by two chitinous cutting plates in the buccal cavity and fused male copulatory spicules, is the causative agent of necatoriasis, a hookworm disease prevalent in the Americas as well as in the tropical regions of Africa, southern Asia. and Polynesia. The adult parasites attached to the villi of the small intestines will suck blood causing abdominal discomfort, diarrhea and cramps, anorexia, weight loss, and in advanced disease, hypochromic microcytic anemia. Hookworm infections in man, especially in children, are one of the leading causes of iron-deficiency anemia resulting directly from intestinal capillary blood loss following the feeding activities of fourth-stage (L-4) larva and adult worms. Another clinical manifestation often associated with hookworm infections is cutaneous larva migrans (CLM). It is a well recognized, usually self-limiting condition caused by the infectious larvae of nematodes. CLM is characterized by skin eruption and represents a clinical description rather than a definitive diagnosis. Of the hookworm parasites, the dog and cat worm Ancylostoma braziliense is the most common causing CLM, although many other species have been implicated. The major subject of this review article will be discussion of the evolution of therapies and treatment of human necatoriasis and the development of experimental infections with N. americanus. Difference in the clinical efficacies of mebendazole and albendazole will be discussed along with drug resistance of N. americanus. |
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| Molecular studies |
| Title: | Hookworm aspartic protease, Na-APR-2, cleaves human hemoglobin and serum proteins in a host-specific fashion |
| Authors: | Williamson, AL Brindley, PJ Abbenante, G Datu, BJD Prociv, P Berry, C Girdwood, K Pritchard, DI Fairlie, DP Hotez, PJ Zhan, B Loukas, A |
| Journal: | J. Infect. Dis. (2003) 187(3):484-494 |
| Abstract: + | Hookworms are voracious blood-feeders. The cloning and functional expression of an aspartic protease, Na-APR-2, from the human hookworm Necator americanus are described here. Na- APR-2 is more similar to a family of nematode-specific, aspartic proteases than it is to cathepsin D or pepsin, and the term "nemepsins" for members of this family of nematode- specific hydrolases is proposed. Na-apr-2 mRNA was detected in blood-feeding, developmental stages only of N. americanus, and the protease was expressed in the intestinal lumen, amphids, and excretory glands. Recombinant Na-APR-2 cleaved human hemoglobin (Hb) and serum proteins almost twice as efficiently as the orthologous substrates from the nonpermissive dog host. Moreover, only 25% of the Na-APR-2 cleavage sites within human Hb were shared with those generated by the related N. americanus cathepsin D, Na-APR-1. Antiserum against Na-APR-2 inhibited migration of 50% of third-stage N. americanus larvae through skin, which suggests that aspartic proteases might be effective vaccines against human hookworm disease. |
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| Title: | Cleavage of hemoglobin by hookworm cathepsin D aspartic proteases and its potential contribution to host specificity |
| Authors: | Williamson, AL Brindley, PJ Abbenante, G Prociv, P Berry, C Girdwood, K Pritchard, DI Fairlie, DP Hotez, PJ Dalton, JP Loukas, A |
| Journal: | Faseb J. (2002) 16(9):U38-U61 |
| Abstract: + | Hookworms routinely reach the gut of nonpermissive hosts but fail to successfully feed, develop, and reproduce. To investigate the effects of host-parasite coevolution on the ability of hookworms to feed in nonpermissive hosts, we cloned and expressed aspartic proteases from canine and human hookworms. We show here that a cathepsin D-like protease from the canine hookworm Ancylosotoma caninum (Ac-APR-1) and the orthologous protease from the human hookworm Necator americanus (Na-APR-1) are expressed in the gut and probably exert their proteolytic activity extracellularly. Both proteases were detected immunologically and enzymatically in somatic extracts of adult worms. The two proteases were expressed in baculovirus, and both cleaved human and dog hemoglobin (Hb) in vitro. Each protease digested Hb from its permissive host between twofold (whole molecule) and sixfold (synthetic peptides) more efficiently than Hb from the nonpermissive host, despite the two proteases' having identical residues lining their active site clefts. Furthermore, both proteases cleaved Hb at numerous distinct sites and showed different substrate preferences. The findings suggest that the paradigm of matching the molecular structure of the food source within a host to the molecular structure of the catabolic proteases of the parasite is an important contributing factor for host-parasite compatibility and host species range. |
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| Title: | Na-ctl-2, a cDNA encoding a C-type lectin expressed exclusively in adult Necator americanus hookworms |
| Authors: | Loukas, A Brown, AP Pritchard, DI |
| Journal: | DNA Seq. (2002) 13(1):61-65 |
| Abstract: + | C-type lectins (C-TLs) are carbohydrate-binding proteins central to diverse physiological processes including immunity, venom-induced haemostasis and wound repair. Here we describe the cloning of Na-ctl-2, a cDNA encoding a secreted C-TL from the human hookworm Necator americanus. The transcript was detected in mRNA from adult worms but not infective larvae. The cDNA encoded an N-terminal secretory signal peptide followed by a long-form C-TL domain with sequence similarity to C-TL-like proteins from Caenorhabditis elegans and mammalian antigen presenting cell receptors, suggesting that hookworms might utilise this class of lectin to interrupt anti-parasite immune responses or interfere with host clotting mechanisms. This is the first report of a full-length cDNA encoding a lectin from hookworms. The unusually skewed representation of this protein family within different nematode genera and its subsequent impact on the evolution of nematode parasitism is discussed. |
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| Title: | Molecular characterization of Ancylostoma inhibitors of coagulation factor Xa - Hookworm anticoagulant activity in vitro predicts parasite bloodfeeding in vivo |
| Authors: | Harrison, LM Nerlinger, A Bungiro, RD Cordova, JL Kuzmic, P Cappello, M |
| Journal: | J. Biol. Chem. (2002) 277(8):6223-6229 |
| Abstract: + | Bloodfeeding hookworms, which currently infect over a billion people in the developing world, are a leading cause of gastrointestinal hemorrhage and iron deficiency anemia. The major anticoagulant inhibitor of coagulation factor Xa has been identified from the hookworm parasite Ancylostoma ceylanicum using reverse transcription PCR and 3'-rapid amplification of cDNA ends. This is the first anticoagulant cloned from a hookworm species for which humans are recognized permissive hosts. Despite similar to50% amino acid similarity, A. ceylanicum anticoagulant peptide 1 (AceAP1) is both immunologically and mechanistically distinct from AcAP5, its homologue isolated from the dog hookworm Ancylostoma caninum. Studies using plasma clotting times and single stage chromogenic assays of factor Xa activity have demonstrated that the recombinant AceAP1 protein is substantially less potent than AcAP5 and that soluble whole worm protein extracts of adult A. ceylanicum possess less anticoagulant activity than extracts of A. caninum. These values correlate with previously reported differences in bloodfeeding capabilities between these two species of hookworm, suggesting that factor Xa inhibitory activity is predictive of hookworm bloodfeeding capabilities in vivo. These fundamental differences in the mechanism of action and immunoreactivity of the major anticoagulant virulence factors from related Ancylostoma hookworm species may have significant implications for human vaccine development. |
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| Title: | The human hookworm pathogen Necator americanus induces apoptosis in T lymphocytes |
| Authors: | Chow, SC Brown, A Pritchard, D |
| Journal: | Parasite Immunol. (2000) 22(1):21-29 |
| Abstract: + | In the present study, we demonstrate that Jurkat T cells undergo apoptosis when cocultured with the human hookworm Necator americanus. Pro-apoptotic activity was dose-dependent and readily detectable in hookworm secretions. This pro- apoptotic effect appears to be specific to cells of T lineage since the monocytic cell line, THP-1, the erythroleukaemic cell line, K562, and the basophil cell line, KU812, were unaffected The induction of apoptosis in Jurkat T cells by the hookworm secretions did not involve cell activation or the Fas/Fas ligand interaction. In addition, the pro-apoptotic effect of the hookworm, or its secretions, was observed with activated human T cells but not with resting peripheral blood lymphocytes. These findings support the hypothesis that the hookworms' ability to recurrently infect humans is due to the parasite creating a site of 'immune privilege' around itself This strategy promptly induces any reactive host leucocytes infiltrating the site of parasite colonization to undergo apoptosis, which reduces inflammation and renders the infection relatively asymptomatic. |
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| Related |
| Title: | Genes on chromosomes 1 and 13 have significant effects on Ascaris infection |
| Authors: | Williams-Blangero, S VandeBerg, JL Subedi, J Aivaliotis, MJ Rai, DR Upadhayay, RP Jha, B Blangero, J |
| Journal: | Proc. Natl. Acad. Sci. U. S. A. (2002) 99(8):5533-5538 |
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| Title: | Transcriptome-based antigen identification for Neisseria meningitidis |
| Authors: | Kurz, S Hubner, C Aepinus, C Theiss, S Guckenberger, M Panzner, U Weber, J Frosch, M Dietrich, G |
| Journal: | Vaccine (2003) 21(7-8):768-775 |
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| Title: | Transcriptome analysis of Neisseria meningitidis during infection |
| Authors: | Dietrich, G Kurz, S Hubner, C Aepinus, C Theiss, S Guckenberger, M Panzner, U Weber, J Frosch, M |
| Journal: | J. Bacteriol. (2003) 185(1):155-164 |
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