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PubMed1991

Guatemalan human onchocerciasis. II. Evidence for IgG3 involvement in acquired immunity to Onchocerca volvulus and identification of possible immune-associated antigens.

Ag-specific isotypic differences in immune response to Onchocerca volvulus Ag were assessed for 778 long term residents of endemic Guatemalan areas by quantitative ELISA with 5-min incubation steps and immunoblot. The study population was separated into five groups based on clinical status: N+F+, N+F-, N-F+, N-F-H+, and N-F-H-, where N = O. volvulus adults (nodule), F = microfiladermia, and H = history of O. volvulus infection. A subset of 44 individuals with high exposure to onchocerciasis from the N-F-H- group were critically evaluated and designated as "putatively immune." IgG1 reactivity to O. volvulus Ag was elevated in the majority of infected persons, but not in putatively immune individuals. Specific IgG3 levels, however, were equally elevated in all groups. The majority of N+F- persons also had elevated IgG1 levels, but they were lower than those found in F+ persons. IgG3 reactivities to a group of antigens at 20 kDa (GP20) were seen in many uninfected persons and some N+F- persons. In contrast, most F+ persons, react to this Ag with IgG1 and not IgG3. A mangabey inoculated with the infectious larval stage of O. volvulus (L3), but showed no signs of infection, began to recognize GP20 at 2 wk postinoculation. Early recognition of GP20 was possibly elicited by the larval stage. Purified nodule Ag from N+F+ individuals contained GP20, however, identical nodule Ag prepared from N+F- individuals did not. These data suggest that GP20 Ag may be common to both uterine microfilaria and the infectious larval stages. The fact that GP20 is predominantly recognized by IgG3 in putatively immune persons and some N+F- persons suggests that this increased IgG3 activity may be important in acquired immunity to onchocerciasis.

Adolescent↗

PubMed1991

Migration and death of skin-dwelling Onchocerca volvulus microfilariae after treatment with ivermectin.

The effects of a single dose of ivermectin (122-200 micrograms/kg) on Onchocerca volvulus microfilariae (mf) in skin and lymph nodes were studied histologically in a qualitative and quantitative manner over seven days after treatment. Ivermectin caused mf to move from the subepidermal layer into the deeper layers of the dermis, subcutaneous fat and connective tissue, and the regional lymph nodes. No mf were seen migrating upwards through the epidermis. Dead mf were not seen before 24 hr and the numbers found dead in the dermis were far fewer than the total numbers in the skin before treatment. Inflammatory cellular reaction around dead mf in the tissues was usually minimal. The results suggest that most of the mf which disappear from the skin may be destroyed in the lymph nodes and that the histological reaction excited by mf dying under ivermectin is less violent than that after diethylcarbamazine.

Adult↗

PubMed1992

Onchocerca volvulus DNA probe classification correlates with epidemiologic patterns of blindness.

Onchocerciasis, or river blindness, results from infection with Onchocerca volvulus. The parasite is endemic to West Africa, in both rain forest and savanna bioclimes. Several lines of evidence suggest that different strains of the parasite exist in the rain forest and savanna. Furthermore, epidemiologic evidence indicates that ocular onchocerciasis is most severe in savanna regions. This has led to the hypothesis that there is a strain association with ocular pathology. To test this hypothesis, parasites from villages in which severe and mild onchocerciasis were endemic were classified with two strain-specific DNA probes. A strong correlation (P less than .001) was found between disease severity and probe recognition, supporting the hypothesis that pathogenicity is strain related. The results suggest that pFS-1 and pSS-1BT may be used to predict the pathogenic potential of parasite populations throughout much of West Africa.

Africa, Western↗

PubMed1997

Molecular characterization and expression of Onchocerca volvulus glutathione reductase.

Glutathione metabolism represents a potential target for anti-parasite drug design. The central role of glutathione reductase (GR) in maintenance of the thiol redox state and in anti-oxidative defence has to be evaluated in more detail in order to establish the essential function of this enzyme for the survival of the filarial parasite Onchocerca volvulus. The O. volvulus GR (OvGR) gene was cloned and sequenced. The gene is composed of 13 exons and 12 introns and spans 4065 bp. The first intron is located within the 5'-untranslated region of the gene, 16 nucleotides upstream of the translation initiation codon. Southern-blot analysis and structural characterization of the genomic sequence indicate that OvGR is encoded by a single-copy gene. Isolation of various cDNA clones revealed a polymorphism of polyadenylation initiation with no consensus polyadenylation sites in any of the cDNAs analysed. The entire cDNA is 1977 bp long and carries the nematode-specific spliced leader sequence SL1 at its 5' end, 236 nucleotides upstream of the first in-frame methionine. The cDNA codes for a polypeptide of 462 amino acids with 53.5% sequence identity with human GR (HsGR). A total of 18 out of 19 residues contributing to glutathione binding are identical in OvGR and HsGR. However, one of the arginine residues (Arg-224 in HsGR) involved in discrimination between NADPH and NADH in all known GRs is substituted by tryptophan (Trp-207 in OvGR). The coding region of OvGR was expressed in Escherichia coli as a histidine-fusion protein, and it was established that the parasite protein still favours the binding of NADPH (Km 10.9 microM) over NADH (Km 108 microM). The histidine-fusion protein has a subunit size of 54 kDa and is active as a homodimer of 110 kDa.

Amino Acid Sequence↗

PubMed1982

Effects of temperature on development of Onchocerca volvulus in Simulium ochraceum, and longevity of the simuliid vector.

The effects of temperature on the development of Onchocerca volvulus in Simulium ochraceum, and on the vector's longevity were studied under simulated environmental conditions in the laboratory. When S. ochraceum (which had fed on a person infected with O. volvulus) were maintained at different, constant temperatures (10-30 C), larvae developed to the infective stage between 20 and 28 C. The time required for development to the infective stage depended on the relationship of y = -0.3760 + 0.0222x (y = velocity in development; x = rearing temperature). However, larval development to the infective stage occurred in all groups kept at different temperatures by day and by night (25 C during the day and 10-18 C during the night), although the developmental period was prolonged (10 days in the group held at 25/18 C, and 13 days in other groups). The percentage of females harboring infective larva(e) among those maintained was highest at a constant temperature of 22 C (21.9%), followed by 15.0% at 25 C. When S. ochraceum females were held at day/night differing temperatures, much higher rates were observed at 25/16 C (30.0%) and at 25/14 C (23.0%). Our results suggest that the distribution of onchocerciasis in Guatemala may be related to ambient temperature and to day/night temperature cycles.

Animals↗

PubMed1978

Acid phosphatase activity in the larval stages of Onchocerca volvulus developing in the vector Simulium damnosum.

The staining patterns of acid phosphatase activity of the various larval stages of Onchocerca volvulus from experimentally infected Simulium damnosum s.l. have been described. The enzyme activity was localized in the anal vesicle/pore area of the first-stage larva, in the anal vesicle and intestine of the secong-stage larva and all over the body in the third-stage larva. Early third-stage larvae could be differentiated from late third-stage infective larvae by the presence of pronounced enzyme activity in the rectum area of the former. There were no detectable differences in the staining patterns between the forest and Sudan-savanna strains of O. volvulus developing in S. damnosum.

Acid Phosphatase↗

PubMed2001

Modulation of human T cell responses and macrophage functions by onchocystatin, a secreted protein of the filarial nematode Onchocerca volvulus.

Immune responses of individuals infected with filarial nematodes are characterized by a marked cellular hyporesponsiveness and a shift of the cytokine balance toward a Th2/Th3 response. This modulation of cellular immune responses is considered as an important mechanism to avoid inflammatory immune responses that could eliminate the parasites. We investigated the immunomodulatory potential of a secreted cysteine protease inhibitor (onchocystatin) of the human pathogenic filaria Onchocerca volvulus. Recombinant onchocystatin (rOv17), a biologically active cysteine protease inhibitor that inhibited among others the human cysteine proteases cathepsins L and S, suppressed the polyclonally stimulated and the Ag-driven proliferation of human PBMC. Stimulated as well as unstimulated PBMC in the presence of rOv17 produced significantly more IL-10, which was paralleled in some situations by a decrease of IL-12p40 and preceded by an increase of TNF-alpha. At the same time, rOv17 reduced the expression of HLA-DR proteins and of the costimulatory molecule CD86 on human monocytes. Neutralization of IL-10 by specific Abs restored the expression of HLA-DR and CD86, whereas the proliferative block remained unaffected. Depletion of monocytes from the PBMC reversed the rOv17-induced cellular hyporeactivity, indicating monocytes to be the target cells of immunomodulation. Therefore, onchocystatin has the potential to contribute to a state of cellular hyporesponsiveness and is a possible pathogenicity factor essential for the persistence of O. volvulus within its human host.

Animals↗

PubMed1991

Viability of adult Onchocerca volvulus after six 2-weekly doses of ivermectin.

Ivermectin is a safe, effective microfilaricide and microfilarial suppressant for Onchocerca volvulus; but in single doses of 100-200 micrograms/kg body weight it has no macrofilaricidal action. The present trial aimed to determine whether 6 doses of 100 micrograms/kg ivermectin, given at 2-week intervals, would kill the adult worms. Eighty-two nodules from 28 otherwise healthy adult male Liberian patients treated with this ivermectin schedule, and 102 nodules from a similar group of 25 control patients, were removed four months after the last dose of ivermectin. They were coded and assessed in a masked fashion either by routine histology or by examination of whole worms extracted from the nodules after collagenase digestion. The drug had no visible effect on adult male worms. More adult female worms were assessed as moribund or dead in the ivermectin-treated group than in the control group (for the collagenase digests P = 0.09; for the histological assessment P = 0.47). The data suggest that repeated dosage with ivermectin may lead to a slow attrition of some female worms and this possibility should be investigated in patients receiving regular doses every 3, 6 or 12 months as part of onchocerciasis control programmes.

Adult↗

PubMed2000

Identification of potential vaccine and drug target candidates by expressed sequence tag analysis and immunoscreening of Onchocerca volvulus larval cDNA libraries.

The search for appropriate vaccine candidates and drug targets against onchocerciasis has so far been confronted with several limitations due to the unavailability of biological material, appropriate molecular resources, and knowledge of the parasite biology. To identify targets for vaccine or chemotherapy development we have undertaken two approaches. First, cDNA expression libraries were constructed from life cycle stages that are critical for establishment of Onchocerca volvulus infection, the third-stage larvae (L3) and the molting L3. A gene discovery effort was then initiated by random expressed sequence tag analysis of 5,506 cDNA clones. Cluster analyses showed that many of the transcripts were up-regulated and/or stage specific in either one or both of the cDNA libraries when compared to the microfilariae, L2, and both adult stages of the parasite. Homology searches against the GenBank database facilitated the identification of several genes of interest, such as proteinases, proteinase inhibitors, antioxidant or detoxification enzymes, and neurotransmitter receptors, as well as structural and housekeeping genes. Other O. volvulus genes showed homology only to predicted genes from the free-living nematode Caenorhabditis elegans or were entirely novel. Some of the novel proteins contain potential secretory leaders. Secondly, by immunoscreening the molting L3 cDNA library with a pool of human sera from putatively immune individuals, we identified six novel immunogenic proteins that otherwise would not have been identified as potential vaccinogens using the gene discovery effort. This study lays a solid foundation for a better understanding of the biology of O. volvulus as well as for the identification of novel targets for filaricidal agents and/or vaccines against onchocerciasis based on immunological and rational hypothesis-driven research.

Animals↗

PubMed2004

Wolbachia endosymbionts of Onchocerca volvulus express a putative periplasmic HtrA-type serine protease.

Wolbachia are intracellular bacteria of many filarial nematodes. A mutualistic interaction between the endobacteria and the filarial host is likely, because the clearance of Wolbachia by tetracycline leads to the obstruction of embryogenesis and larval development. Databases were searched for exported molecules to identify candidates involved in this mutualism. Fragments of a Wolbachia serine protease from the human filarial parasite Onchocerca volvulus were obtained (Wol-Ov-HtrA) by the use of a PCR technique and primers based on the Rickettsia prowazekii genome. The deduced amino acid sequence exhibited 87% and 81% identity to the homologous Wolbachia proteases identified from Brugia malayi and Drosophila melanogaster, respectively. The full-length cDNA encodes 494 amino acids with a calculated mass of 54 kDa. Three characteristic features, (i) a catalytic triad of serine proteases, (ii) two PDZ domains and (iii) a putative signal peptide, classify the endobacterial protein as a member of the periplasmic HtrA family of proteases known to express chaperone and regulator activity of apoptosis. Using a rabbit antiserum raised against a recombinantly expressed 33-kDa fragment of Wol-Ov-HtrA, strong labelling of the antigen was found associated with endobacteria in hypodermis, oocytes, zygotes, all embryonic stages and microfilariae of O. volvulus. Staining of hypodermal cytoplasm surrounding the endobacteria indicated a possible release of the protein from the Wolbachia. The demonstration of Wol-Ov-HtrA-reactive IgG1 antibodies in sera of O. volvulus-infected persons indicated the exposure to the protein and its recognition by the human immune system. Wol-Ov-HtrA is a candidate for an exported Wolbachia protein that may interact with the filarial host metabolism.

Amino Acid Sequence↗

PubMed2004

The safety, tolerability and pharmacokinetics of levamisole alone, levamisole plus ivermectin, and levamisole plus albendazole, and their efficacy against Onchocerca volvulus.

Two randomized, double-blind, placebo-controlled trials, in which levamisole (2.5 mg/kg) was given alone or co-administered with ivermectin (200 microg/kg) or albendazole (400 mg), were conducted. In Trial 1, safety and drug-drug interaction were explored in 42 healthy male volunteers. During Trial 2, the safety of the same treatment regimens and their efficacy against the adult worms and microfilariae of Onchocerca volvulus were investigated in 66 infected subjects of both sexes. Safety was determined from the results of detailed clinical and laboratory examinations before treatment, during hospitalization and on day 30. The pharmacokinetic parameters for levamisole alone and the combinations were determined in Trial 1 and then compared with historical data for ivermectin and albendazole, given as single agents, to determine if drug-drug interaction had occurred. The level of efficacy against the adult worms was determined by the examination of histology sections of nodules excised 6 months posttreatment and from the changes seen in the levels of microfilaridermia within a year of treatment. Microfilaricidal efficacy was estimated from the reductions in the levels of microfilaridermia between day 0 (1 day pre-treatment) and day 30. Although the regimens were generally well tolerated, there were unexpected adverse effects in both healthy volunteers and infected subjects. Clinically significant drug-drug interactions resulted in an increase in the bio-availability of ivermectin but a reduction in that of albendazole when these drugs were co-administered with levamisole. Levamisole given alone or with albendazole had little effect on O. volvulus. The combination of levamisole with ivermectin was neither macrofilaricidal nor more effective against the microfilariae and the adult worms than ivermectin alone. The pathogenesis of the adverse events and the drug-drug interactions are discussed.

Adolescent↗

PubMed2004

Identification of variant ABC-transporter genes among Onchocerca volvulus collected from ivermectin-treated and untreated patients in Ghana, West Africa.

Treatment with ivermectin (IVM) is known to cause a loss of polymorphism at certain loci of the beta-tubulin, gamma-aminobutyric-acid-receptor, glutamate-gated-chloride-channel and ATP-binding-cassette (ABC) transporter genes of IVM-resistant Haemonchus contortus. The genetic variation of four ABC-transporter homologues from Onchocerca volvulus was therefore investigated, to determine if any change in genetic polymorphism occurs in these genes following repeated treatment with IVM. Samples were collected in the Northern, Brong-Ahafo and Volta regions of Ghana, in 1999 and 2002; nodules containing adult O. volvulus were removed from subjects who had either received multiple IVM treatments or never taken IVM. The ATP-binding domains of four ABC-transporter genes (OvMDR-1, OvMDR-3, OvABC-1 and OvABC-6) were amplified from individual O. volvulus and examined for polymorphism, using single-strand-conformation-polymorphism (SSCP) analysis. In the samples collected in 1999, OvMDR-1 and OvABC-1 showed significant reduction in polymorphism following IVM treatment whereas OvABC-6 and OvMDR-3 were not found to be polymorphic. The samples collected in 2002 also showed a reduction in polymorphism for both OvMDR-1 and OvABC-1. Several single-nucleotide polymorphisms, which resulted in either amino-acid-replacement substitutions or nonsense mutations, were identified in the alleles of OvMDR-1 and OvABC-1.

ATP-Binding Cassette Transporters↗

PubMed2003

Experimental studies on the transmission of Onchocerca volvulus by its vector in the Sanaga valley (Cameroon): Simulium squamosum B. Intake of microfilariae and their migration to the haemocoel of the vector.

As large-scale ivermectin distribution is becoming the mainstay of onchocerciasis control in Africa, the issue of its impact on local transmission is increasing in importance. The vector competence of Simulium squamosum B in the severe focus of the Sanaga valley, Cameroon, was therefore investigated, by feeding 1320 flies on 14 carriers of Onchocerca volvulus microfilariae (mff). The results enabled the relationships between skin microfilarial load, microfilarial intake by the flies, the proportion and mean number of ingested mff that succeed in reaching the fly's haemocoel, and the frequency distribution of the ingested mff to be described, as functions of time post-engorgement (p.e.) and parasite density (while taking account of possible measurement error in the predictor variable). The proportion of flies with haemocoelic mff and the mean number of mff/fly increased up to 3 h p.e. The proportion of flies with ingested mff was non-linearly related to mean intake, via the negative-binomial distribution, with the overdispersion parameter k best described as an increasing (power) function of the mean. Approximately one in every three ingested mff escaped imprisonment by the peritrophic matrix, irrespective of the skin microfilarial load or the intake of mff. The relationship between successful and input mff is nearly linear (indicating proportionality) in S. squamosum B. These results are compared with those from O. volvulus-S. damnosum s.l. combinations in other West African foci.

Adolescent↗

PubMed1999

Distribution of the blinding and nonblinding strains of Onchocerca volvulus in Nigeria.

Onchocerciasis remains an important public health problem throughout much of sub-Saharan Africa. Nigeria is the country whose population is most afflicted by onchocerciasis; however, little is known concerning the epidemiology of onchocerciasis in this country. Previous studies demonstrated that onchocerciasis in West Africa exists in two forms, which differ in their clinical and epidemiologic characteristics. This is believed to be due to the existence of 2 strains of Onchocerca volvulus, the causative agent of onchocerciasis. The O-150 polymerase chain reaction has been developed to differentiate these 2 strains, and this method has been used to map the distribution of the blinding and nonblinding strains of O. volvulus in Nigeria. The strain distribution is consistent with what is known concerning the ecology and epidemiology of onchocerciasis in this country. The results also suggest that migration may be affecting the historic distribution of the 2 strains of the parasite in Nigeria.

Animals↗

PubMed1991

Observations and reflections on the immature stages of Onchocerca volvulus in the human host.

Knowledge of the morphology, migrations and development rates of the L3, L4 and prepubertal L5 stages of Onchocerca volvulus in the vertebrate host is an essential prerequisite to work vaccine development of chemoprophylaxis. After a brief review of the scanty literature available on this subject a description is given of two immature worms, one male and one female, found in an O. volvulus nodule from Guatemala. The male, which measured 12 mm x 40 micron(s), had fine regular transverse cuticular annulations, two prominent spicules, and an undifferentiated testis. The female, which measured 20 mm x 40 micron(s), had not yet developed cuticular ridges but showed a vulva, gut, and two rudimentary genital tracts. It is thought that these worms may have been six to 12 weeks old. The likely course of the early development of O. volvulus in the vertebrate host is discussed, based on analogy with O. lienalis in cattle; and some of the factors to be taken into account when pursuing the search for O. volvulus immatures are described.

Animals↗

PubMed1990

Onchocerca volvulus: molecular cloning, primary structure, and expression of a microfilarial surface-associated antigen.

Although the filarial nematode parasite Onchocerca volvulus is an important human pathogen in large areas of Africa and Latin America, little is known of the molecular interactions that govern the clinical status of patients with this chronic, debilitating disease. As a step toward defining the parasite molecules important to the immunobiology of host-parasite interactions, we have identified and cloned a major surface-associated antigen expressed by O. volvulus microfilariae. Radiolabeling experiments demonstrated that O. volvulus microfilariae have a limited repertoire of peptides at the surface. Prominent among these labeled peptides is an 18-kDa component. Immunological cross-reactivity between a surface-associated component of Dirofilaria immitis microfilariae and the 18-kDa surface-associated molecule from O. volvulus was exploited in a strategy to clone this potentially important O. volvulus microfilarial antigen. The cross-reacting antibodies were used to immunoscreen O. volvulus cDNA expression libraries. One clone, M2f.e, contained an open reading frame of 495 bp encoding an 18.1-kDa protein (OVMS18). Antibodies produced against the expression product of M2f.e recognized an 18-kDa component in extracts of O. volvulus microfilariae and bound to the surface of intact O. volvulus and D. immitis microfilariae. Southern blot analyses showed that M2f.e-like sequences are present in the genomic DNA of a number of filarial nematode species, but not in DNAs from nonfilarial nematode species.

Amino Acid Sequence↗

PubMed2006

Reduction in the prevalence and intensity of infection in Onchocerca volvulus microfilariae according to ethnicity and community after 8 years of ivermectin treatment on the island of Bioko, Equatorial Guinea.

Bioko is the only island known in the world with endemic onchocerciasis. The island's rural communities consist of villages and cocoa plantations inhabited by Bubi and Fang ethnic groups. The aim of this study was to evaluate the impact of 8 years of vertical ivermectin distribution on the prevalence and intensity of Onchocerca volvulus infection in the rural population by means of pre- (1989) and post-long term treatment (1998) epidemiological surveys. In both surveys, the entire population of 12 randomly selected communities (1723 and 1082 individuals) was examined. The mean ivermectin therapeutic coverage for the 8 years was 53.2%. Iliac crest skin snips were used for differential diagnosis between O. volvulus and Mansonella streptocerca. The crude O. volvulus infection prevalence before ivermectin intervention was 74.5% (1284/1723); after the intervention it was 38.4% (415/1082). The Community Microfilarial Load (CMFL) before and after ivermectin intervention was 28.29 microfilariae/snip vs. 2.32 microfilariae/snip. The reduction in prevalence and CMFL after eight annual rounds of ivermectin treatment corroborates the drug microfilaricidal activity and good tolerability. In the pre-treatment survey, the prevalence was higher in the Bubi group (77.1%, 1126/1461); post-treatment it was higher among the Fang (51.1%, 92/180). The reduction in prevalence and intensity of O. volvulus infection differed between ethnic groups and communities.

Adolescent↗

PubMed1988

Large scale production of the vertebrate infective stage (L3) of Onchocerca volvulus (Filarioidea: Onchocercidae).

Laboratory-derived Simulium yahense and S. sanctipauli females were used to produce large numbers of Onchocerca volvulus infective stage larvae (L3) for use in assessing the possible chemoprophylactic potential of ivermectin in the chimpanzee model. Engorgement rates and subsequent post-prandial survival were correlated with the time at which adult flies were offered a carbohydrate source following emergence and the age of flies that fed on microfiladermic volunteers.

Animals↗