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PubMedDate not supplied

Delayed-type hypersensitivity reactions to Onchocerca volvulus antigens in exposed and non-exposed African individuals.

Although considered of critical importance, the mode of helper T-lymphocyte function in Onchocerca volvulus infection is still unclear including the role of the Th1/Th2 dichotomy. We studied the delayed-type hypersensitivity (DTH) reaction, which is the classical Th1 response, to O. volvulus antigens in Africans exposed and not exposed to the infection. DTH reactions were found in a small percentage of patients with generalized onchocerciasis, but in a high percentage of patients with localized onchocerciasis, in putatively immune subjects, and also in non-exposed individuals, which may be due to cross-reactivity with other nematodes. These findings support the notions of (i) prenatal influence of maternal O. volvulus infection preventing development of Th1 responses and/or (ii) suppression of Th1 responses by the infection itself.

Adolescent↗

PubMed1993

Absence of sperm from the seminal receptacle of female Onchocerca volvulus following multiple doses of ivermectin.

It is already known that multiple doses of ivermectin have a profound effect on embryonic development in Onchocerca volvulus and that this appears to operate mainly at the single cell stage. To investigate this further, we examined adult female O. volvulus originating from patients treated either with placebo or one, four or five doses of ivermectin. The reproductive organs were dissected out of the worm and examined for evidence of oogenesis and for the quantity of sperm and oocytes in the seminal receptacles. A single dose of ivermectin had no measurable effect on oogenesis or on the amount of sperm and oocytes compared to placebo. However after multiple doses of ivermectin a significantly lower proportion of seminal receptacles contained sperm and there was a significantly higher proportion of ovaries with impaired oogenesis compared to placebo. It is concluded that the reduction in the number of multicellular embryonic stages from worms exposed to multiple doses of ivermectin is due, at least in part, to a major reduction in the effective insemination of female worms and to a minor impairment of oogenesis.

Animals↗

PubMed1996

Characterization of the arylalkylamine N-acetyltransferase in Onchocerca volvulus.

The characteristics and kinetic properties of an arylalkylamine N-acetyltransferase were studied in partially purified preparations of the human filarial parasite Onchocerca volvulus. The enzyme, which had a relative molecular mass (M(r)) of 37-38 kDa, catalyzed the acetylation of arylalkylamines but did not accept arylamines or polyamines as substrates. The optimal pH for enzyme activity was found to be 8.5 in TRIS-HCI. The apparent Michaelis constant (K(m)) and maximum velocity (Vmax) determined from Lineweaver-Burk plots for tryptamine were 1.8 microM and 29 nmol min-1 mg protein-1, respectively. Except for the catecholamines, the other arylalkylamines such as 5-hydroxytryptamine (5-HT), tyramine, and octopamine similarly exhibited high affinities and reaction rates. Whereas the enzyme is inhibited by metals and p-chloro-mercuribenzoate, it is inactivated neither by amethopterin nor by cystamine and is thereby distinguished from the mammalian arylamine N-acetyltransferase. Like other N-acetyltransferases whose function is the regulation of intracellular amine levels, the enzyme may have a role in the inactivation of excess biogenic amine in this parasite.

Animals↗

PubMed2001

Development of Onchocerca volvulus (Filarioidea: Onchocercidae) in the West African black fly Simulium yahense (Diptera: Simuliidae) in Liberia.

Simulium yahense black flies infected with microfilaria of Onchocerca volvulus were kept in a defined insectary environment in Liberia, West Africa. A daily sample of infected flies was dissected for larvae developing in the thoracic muscles and examined for growth in stadial development. Microfilariae ingested by black flies transformed to the L1 larval stage without molting. Successive larval development included molting to the L2 stage and, finally, to the L3 stage, which was infective in humans. The cephalic cap, consisting of a laterally located hook and central stoma, occurs in the first larval stage. The caudal appendix and the laterally located anal opening are apparent in the L1 larva. In the L2 stage, the cephalic cap is lost and the large circular stoma becomes surrounded with elevated flaps. The caudal appendix was lost after larvae molted to the L3 stage, and in its place, 3 terminal papillae developed. Sense organs, such as 2 opposing phasmids and 8 papillae that were arranged into 2 circles, developed in the cephalic region of the L3 larva. The evidence of pathological consequences due to the presence of the L3 larva in the fly host are illustrated and discussed.

Animals↗

PubMed2005

Genetic polymorphism of the beta-tubulin gene of Onchocerca volvulus in ivermectin naïve patients from Cameroon, and its relationship with fertility of the worms.

Observations of low response of patients infected with Onchocerca volvulus to ivermectin suggest that the parasite may be under a selection process toward potential resistance. To limit the extension of this phenomenon, it is crucial to characterize the genes of O. volvulus that are involved. For this, O. volvulus adult worms collected before the introduction of ivermectin in an onchocerciasis endemic area of central Cameroon were genotyped for beta-tubulin. To derive a baseline to investigate the selective pressure of ivermectin, we analysed (1) the frequency distribution of the beta-tubulin alleles, and (2) the relationship between the different beta-tubulin related genotypes and the fertility status of the female worms. The frequency of allele b of the beta-tubulin gene was very low, as it was observed in West Africa. We observed a deficit of heterozygous female worms leading to Hardy Weinberg disequilibrium, which might be explained by a shorter life-span of these worms compared to the homozygous worms. Unexpectedly, our results also show that the heterozygous female worms were much less fertile than the homozygotes: more than two thirds of the homozygotes were fertile, whereas only 37% of the heterozygotes were fertile. These results will be further considered when analysing post-treatment data.

Adolescent↗

PubMed1992

The effect of repeated doses of ivermectin on adult female Onchocerca volvulus in Sierra Leone.

The effects of single and multiple doses of ivermectin on mortality and morphology were assessed in over 700 female Onchocerca volvulus worms and the effects on embryogenesis were assessed in 490. Nodules were surgically removed from Sierra Leoneans recruited from a double-blind placebo controlled study of ivermectin given at six-monthly intervals. Nodules were digested in collagenase to isolate whole adult worms. After four or five doses of ivermectin there were significant increases in the numbers of discoloured and calcified worms and possibly a trend towards increased mortality, but this was not seen consistently. There was no evidence of a prophylactic effect of the drug. Worms were then homogenised and embryograms constructed. A single dose of ivermectin produced large numbers of degenerating intrauterine microfilariae, but embryonic development occurred normally. After multiple doses we observed almost complete cessation of embryogenesis, with a highly significant decrease in the numbers of viable multicellular embryonic stages, while oocytes appeared to be produced normally. Development is probably impeded at the single cell stage, possibly because of reduced fertilization. In planning the future role of ivermectin as a control measure for onchocerciasis it is crucial to determine if these effects on embryogenesis are reversible.

Adolescent↗

PubMed1997

The Ov20 protein of the parasitic nematode Onchocerca volvulus. A structurally novel class of small helix-rich retinol-binding proteins.

Ov20 is a major antigen of the parasitic nematode Onchocerca volvulus, the causative agent of river blindness in humans, and the protein is secreted into the tissue occupied by the parasite. DNA encoding Ov20 was isolated, and the protein was expressed in Escherichia coli. Fluorescence-based ligand binding assays show that the protein contains a high affinity binding site for retinol, fluorescent fatty acids (11-((5-dimethylaminonaphthalene-1-sulfonyl)amino)undecanoic acid, dansyl-DL-alpha-aminocaprylic acid, and parinaric acid) and, by competition, oleic and arachidonic acids, but not cholesterol. The fluorescence emission of dansylated fatty acids is significantly blue-shifted upon binding in comparison to similarly sized beta-sheet-rich mammalian retinol- and fatty acid-binding proteins. Secondary structure prediction algorithms indicate that a alpha-helix predominates in Ov20, possibly in a coiled coil motif, with no evidence of beta structures, and this was confirmed by circular dichroism. The protein is highly stable in solution, requiring temperatures in excess of 90 degrees C or high denaturant concentrations for unfolding. Ov20 therefore represents a novel class of small retinol-binding protein, which appears to be confined to nematodes. The retinol binding activity of Ov20 could possibly contribute to the eye defects associated with onchocerciasis and, because there is no counterpart in mammals, represents a strategic target for chemotherapy.

Amino Acid Sequence↗

PubMedDate not supplied

Human infection with Onchocerca volvulus does not affect the T helper cell phenotype of the cellular immune response to mycobacterial antigen.

In order to determine whether infection with Onchocerca volvulus might modify the immune response to mycobacterial antigen, the proliferative and cytokine responses of peripheral blood mononuclear cells from 117 persons infected with O. volvulus and 36 non-endemic control subjects were compared. Tuberculin-stimulated cellular proliferative responses and production of Th1-type cytokines (interferon gamma) were reduced in persons infected with O. volvulus compared to controls. However, there was no evidence of polarization of the immune response towards a Th2-type phenotype (interleukin 5) in infected individuals compared to controls.

Adolescent↗

PubMed1985

Immunochemical comparison between worm extracts of Onchocerca volvulus from savanna and rain forest.

Crude phosphate-buffered extracts of adult Onchocerca volvulus from savanna (Mali) and rain forest (Cameroon) areas were comparatively analysed using biochemical and immunological methods. SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and isoelectric focusing revealed only minor differences between the two extracts. Out of 42 bands detectable by SDS-PAGE at least 21 were identified as glycoproteins by their affinity to concanavalin A. High resolution analysis using two dimensional gel electrophoresis (2D-G) showed marked differences in the polypeptide patterns of the two extracts. Some of the over 100 polypeptides demonstrable by Coomassie blue staining (especially at pIs between 4.3 and 5.6 and mol. wts over 64kD) were clearly different when the two extracts were compared. Antigenic differences between the two extracts could be detected by crossed immunoelectrophoresis using a rabbit anti-O. volvulus hyperimmune serum. The comparison by tandem crossed immunoelectrophoresis demonstrated clearly the existence of at least three antigenic differences, four partial identities and 13 antigenic identities between the extracts. For the identification of O. volvulus antigens serologically recognized by infected patients, we combined the 2D-G with an immunoblotting technique using a pool of highly reactive onchocerciasis sera from Mali. IgG binding antigens were then identified by incubating the blot membrane with this serum pool and with 125I-labelled protein A followed by autoradiography. IgE binding antigens were detected using a 125I-labelled anti-human IgE antiserum. Whilst the overall antigenic patterns were similar, there were, however, clear differences between the antigen preparations which gives further evidence for antigenic diversity of O. volvulus from savanna and rain forest areas.

Animals↗

PubMed2003

Angiogenic activity of an Onchocerca volvulus Ancylostoma secreted protein homologue.

Angiogenesis is an important step in the development of ocular onchocercaisis. In previous studies, it has been demonstrated that Onchocerca volvulus homologues of the Ancylostoma secreted protein family have pronounced angiogenic activity. The overall goal of the current study was to determine if this angiogenic effect is exerted through a direct or indirect mechanism. These studies focused on one member of this family, OvASP-2, as this protein is expressed in microfilaria, the stage of the parasite that causes ocular onchocercaisis. Clones encoding truncated and full length open reading frames were expressed as fusion proteins with Escherichia coli maltose binding protein (MBP), and angiogenic activity was compared in vitro and in vivo with MBP alone. Truncated constructs expressing only the first 105 amino acids of OvASP-2 were as active as the full length protein in inducing new blood vessel formation. The full length fusion protein did not stimulate proliferation or production of vascular endothelial growth factor in vascular endothelial cells in vitro, indicating that OvASP-2 does not directly stimulate angiogenesis. Sequence analysis demonstrated that the gene encoding OvASP-2 contained five introns. Sequence comparisons of the genomic loci from West African blinding and non-blinding strains of O. volvulus revealed that some polymorphism existed among the various isolates tested. However, none of these polymorphisms could be used to differentiate the parasite strains, suggesting that qualitative variation in OvASP-2 could not explain the difference in ocular pathogenic potential of the two parasite strains.

Ancylostoma↗

PubMed1993

The Onchocerca volvulus mRNAs for a hsp70, a collagen-like protein and a ribosomal protein possess a 5' spliced leader sequence.

To detect and analyse Onchocerca volvulus mRNAs possessing a spliced leader (SL) sequence, a SL cDNA library was constructed from O. volvulus RNA using a PCR method. Three of the sixty cDNAs analysed displayed significant homology to a known sequence. These cDNAs encode a hsp70, a collagen-like protein and a 60S ribosomal protein. The remaining cDNAs analysed either encoded proteins with no apparent homology to known sequences or they appeared to be generated from RNAs with an internal SL and did not possess an open reading frame.

Amino Acid Sequence↗

PubMed1988

Transmission of Onchocerca volvulus by secondary vectors in Guatemala.

A comprehensive study of the transmission of Onchocerca volvulus at 4 locations in Guatemala with different prevalence rates of onchocerciasis included observations on potential secondary vectors, the most prevalent of which were Simulium metallicum, S. callidum, and S. gonzalezi. Filariae encountered in S. metallicum were primarily of a Dipetalonema-like species, but third-stage larvae indistinguishable from O. volvulus were found in 4 flies of this species. Our findings suggest that O. volvulus may occasionally be transmitted by S. metallicum, but such transmission is likely limited to areas having both a high parasite prevalence maintained by S. ochraceum and a relatively high host-seeking density of S. metallicum. Two third-stage larvae that could not be differentiated from O. volvulus were found once in S. gonzalezi; however, transmission by this species appears to be inconsequential.

Animals↗

PubMedDate not supplied

Impaired antibody responses and loss of reactivity to Onchocerca volvulus antigens by HIV-seropositive onchocerciasis patients.

The impact of concomitant human immunodeficiency virus (HIV) infection on the antibody response of onchocerciasis patients to Onchocerca volvulus antigens (OvAg) was studied by Western blotting and enzyme linked immunosorbent assay (ELISA). Immunoglobulin G (IgG) antibodies in sera from 45 HIV-sero-positive O. volvulus microfilariae (mf) carriers (HIV+/Ov+) recognized significantly fewer distinct O. volvulus antigenic bands, and responded less frequently to all detected bands compared to sera from 61 matched HIV-seronegative mf carriers (HIV-/Ov+). 29% of 31 follow-up sera from the HIV+/Ov+ patients failed to react to many of the antigenic bands recognized by initial sera from the same patients. Among 4 HIV+/Ov+ persons examined for total CD4+ cells, loss of reactivity corresponded with low CD4+ total cell counts. In an OvAg ELISA, sera from the HIV+/Ov+ individuals had significantly lower IgG+IgM antibody levels than sera from the HIV-/Ov+ persons, and the sensitivity of the assay was 87% for the HIV+/Ov+ subjects compared to 100% for those who were HIV-/Ov+. It is concluded that HIV-infected onchocerciasis patients exhibit significantly impaired antibody responses to O. volvulus antigens, and tend to lose their reactivity to these antigens over time due to immune response abnormalities caused by the concomitant HIV infection.

AIDS-Related Opportunistic Infections↗

PubMed1985

Dolichol kinase in Ascaris suum and Onchocerca volvulus.

Dolichol kinase was demonstrated in the microsomal fraction of Ascaris suum and Onchocerca volvulus. The enzyme from nematodes exhibited specificity for CTP as phosphoryl donor and was found to be inhibited by the reaction product CDP. Enzyme activity was optimal at pH 7.4, in the temperature range between 30 degrees and 37 degrees C, and in the presence of 0.5% Triton X-100. In addition, the enzyme was found to depend on divalent cations for activity; Mg2+ being more effective than Mn2+ and Ca2+. The dolichol kinase from both nematodes was shown to be independent of Ca2+-calmodulin for activity. The apparent Km values for dolichol were determined to be 7.5 and 9.0 micrograms ml-1 for the enzyme from A. suum and O. volvulus, respectively. Those for CTP were estimated to be 0.85 and 0.75 mM, respectively.

Animals↗

PubMed1989

Parasitologic survey of Onchocerca volvulus infection in the Nimiyama Chiefdom, Kono District, Sierra Leone.

Infection due to Onchocerca volvulus was investigated in the Nimiyama Chiefdom, Kono District, Sierra Leone, where Simulium damnosum s.l. is known to breed but no data on the prevalence and intensity of O. volvulus infection exists. Of the 735 individuals sampled by the skin snip method in five villages, 471 (64%) were infected. The infection rate for males was significantly (p less than 0.05) higher than that of the females. Two hundred and ninety-one (70.0%) of the 416 males skin snipped and 180 (56.0%) of the 323 of their female cohorts were infected. The intensity of infection increased with age, with the younger cohorts presenting lower microfilarial density (MFD). Palpable nodules were observed in 230 (48.4%) of individuals found positive for skin microfilariae and in 37 (5.0%) individuals found negative for skin microfilariae. It is concluded that O. volvulus infection is mesoendemic in the Nimiyama Chiefdom, with the intensity of infection increasing with age.

Age Factors↗

PubMed1995

Onchocerca volvulus: parasitologic and serologic responses in experimentally infected chimpanzees and mangabey monkeys.

Six chimpanzees (Pan troglodytes) and six mangabey monkeys (Cercocebus atys) were inoculated with Onchocerca volvulus third-stage larvae (L3) of West African origin. Two chimpanzees each received 200, 300, or 400 L3, while three mangabeys each received either 50 or 250 L3. All six chimpanzees became microfilaria positive between 11 and 25 months postinoculation (PI), while two of the six mangabeys were skin-snip positive at 24 and 37 months PI, respectively. All chimpanzees developed antibodies to two native antigens of 14 and 22 kDa and to the recombinant antigens OV16, OC3.6, and OC9.3. Marked antibody responses were observed in the mangabey monkeys, and in general, the responses were similar to those observed in the chimpanzees. However, in the mangabeys, these responses did not generally manifest themselves until later in the infection. The results of this study suggest that in chimpanzees, the smallest inoculum used, 200 L3, was sufficient to initiate consistent infections that had parasitologic and immunologic parameters equivalent to animals inoculated with larger numbers of larvae. Similarly, inoculation of mangabey monkeys with small numbers of larvae appeared to be as likely to establish infection and induce immunologic responses as did inoculation of larger numbers of larvae. Microfilaria-positive chimpanzees and mangabey monkeys were examined by three conventional imaging techniques (X ray, ultrasound, and magnetic resonance imaging (MRI)), but no adult worms or nodules could be identified in any animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Comparison of the sensitivity of different geographical isolates of Onchocerca volvulus microfilariae to ivermectin: effects of exposure to drug on development in the blackfly Simulium ornatum.

Four geographical isolates (Ghana forest, Ghana savannah, Cameroon forest, Guatemala) of Onchocerca volvulus microfilariae (mf) and O. lienalis mf (UK) were examined for their sensitivity to ivermectin by incubation in vitro in drug followed by assessing their ability to develop in the blackfly Simulium ornatum after intrathoracic injection. Parasites were incubated for 30 min in ivermectin (10(-6) to 10(-9) M), which resulted in a concentration dependent decrease in the numbers of parasites surviving and developing in the insect; there were significant reductions in parasite recoveries from all isolates in the 10(-6) M to 5 x 10(-8) M ivermectin groups, but no significant effect was seen following incubation in concentrations of 10(-8) M and below. Experiments consistently demonstrated that the 4 isolates of O. volvulus were similarly sensitive to ivermectin (in the 10(-7) M ivermectin groups there was a reduction of 76.3% to 85.1% in numbers of infective larvae, and 60.9% to 85.5% in numbers of all larval stages, compared to controls); O. lienalis mf were significantly more sensitive (100% reduction in infective larvae, 98.7% reduction in all larval stages). This baseline information on drug sensitivity and techniques should prove useful for examining populations of O. volvulus for possible development of drug resistance in the future.

Animals↗

PubMed2004

RNA interference targeting cathepsin L and Z-like cysteine proteases of Onchocerca volvulus confirmed their essential function during L3 molting.

We describe the successful use of RNA interference (RNAi) to investigate gene function in the human filarial parasite Onchocerca volvulus third-stage larvae (L3). We targeted two specific gene products, the O. volvulus cathepsin L (Ov-CPL) and cathepsin Z-like (Ov-CPZ) cysteine proteases, which were proposed to function during O. volvulus L3 molting. We show that fluorescent-labeled Cy3-dsRNA corresponding to cpl or cpz regions encoding the mature enzymes can enter the larvae. The molting rate of larvae treated overnight with 0.5 mg ml(-1) cpl was reduced by 92% and 86% in comparison to normal control worms. It appeared that although the larvae started the molting process the last stage of molting, ecdysis was inhibited. The effect was gene specific, as larvae that did not molt in the presence of cpl or cpz dsRNA expressed the other cysteine protease, CPZ and CPL, respectively. This was confirmed by immunoelectron microscopy using antibodies directed against each enzyme. Our present study validate conclusively that both enzymes are essential for the molting of O. volvulus L3 to fourth-stage larvae. We also confirmed that the activity of the enzymes is specific to the changes that occur during the molting process on days 1-3, when the separation between the cuticles is in progress. The development of RNAi in O. volvulus L3 could further help study many of the abundant L3 and molting L3 genes identified through the filarial genome project, many of which, although have no attributed function, were identified as vaccine candidates or potential drug targets.

Animals↗