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PubMed1988

Isolation and characterization of expression cDNA clones encoding antigens of Onchocerca volvulus infective larvae.

The isolation of recombinant cDNA clones expressing antigens found in Onchocerca volvulus infective larvae is described. To isolate such clones, an expression cDNA library constructed from adult O. volvulus RNA was screened with antiserum raised against infective larvae. One clone, designated lambda RAL-1 was characterized further. The recombinant antigen produced by lambda RAL-1 stimulates proliferation of peripheral blood mononuclear cells from O. volvulus infected humans. Lambda RAL-1 is derived from a 1450 bases message that encodes a protein with an apparent molecular weight of 42,000 in adult O. volvulus. The inserted DNA of lambda RAL-1 contains an open reading frame of 1008 bp. The amino acid sequence predicted by this open reading frame contains three repeats of the sequence KKPEDWD. The identification of clones such as lambda RAL-1 will provide quantities of purified antigens sufficient to begin to study the immune response to and explore the development of immunity against the infectious form of the parasite.

Amino Acid Sequence↗
PubMed1992

Serological cross-reactivity between a human Ro/SS-A autoantigen (calreticulin) and the lambda Ral-1 antigen of Onchocerca volvulus.

We have cloned and sequenced a 46-kD Ro/SS-A autoantigen gene that is the human homologue of the calcium-binding protein, calreticulin. The sequence of this 46-kD Ro/SS-A protein (calreticulin) has significant homology to lambda Ral-1, a recombinant cDNA clone corresponding to a major antigen of the nematode, Onchocerca volvulus, the infectious agent of onchocerciasis. We therefore sought to determine whether antibodies produced by onchocerciasis patients might crossreact with the human 46-kD Ro/SS-A autoantigen (calreticulin). 20 of 22 sera from Liberian onchocerciasis patients who had no known evidence of autoimmune disease were found to contain antibodies that reacted with the 46-kD Ro/SS-A (calreticulin) by immunoblot analysis. Characteristic of sera reactive with Ro/SS-A antigens, some onchocerciasis sera also immunoprecipitated the Ro/SS-A-associated hY RNAs. In addition, a monoclonal antibody raised against O. volvulus organisms reacted to purified human WiL-2 cell 46 kD Ro/SS-A antigen (calreticulin) by ELISA. These results strongly suggest that onchocerciasis patients produce antibodies that crossreact with the 46-kD human Ro/SS-A autoantigen (calreticulin) and raise the possibility that infectious organisms such as O. volvulus might play a triggering or exacerbating role in the human Ro/SS-A autoimmune response.

Amino Acid Sequence↗
PubMed2003

The co-administration of ivermectin and albendazole--safety, pharmacokinetics and efficacy against Onchocerca volvulus.

A randomized, double-blind, placebo-controlled trial was conducted, to determine whether the co-administration of ivermectin with albendazole is safe and more effective against Onchocerca volvulus than ivermectin alone, and whether a significant pharmacokinetic interaction occurs. Forty-two male onchocerciasis patients received ivermectin (200 mug/kg) alone, albendazole (400 mg) alone or the combination. Safety was determined from the results of detailed clinical and laboratory examinations before treatment, during hospitalization and on day 30. Microfilaricidal efficacy was estimated from the reductions in skin counts between day 0 (pretreatment) and day 30. To determine efficacy against the adult worms, two independent observers examined histology slides prepared from nodules excised on day 180; changes in the skin counts of skin microfilariae between days 30 and 365 provided additional indicators of the level of adulticidal activity. Pharmacokinetic parameters for ivermectin and albendazole sulphoxide were defined over 72 h post-treatment. The co-administration of ivermectin with albendazole did not produce more severe adverse effects than ivermectin alone. Both nodule examiners found that the combination was not macrofilaricidal and that it was not clearly superior to ivermectin alone in the effects on reproductive activity; this was supported by the similar efficacy of the two regimens in the suppression of skin microfilariae. There was no significant pharmacokinetic interaction. Although the co-administration of ivermectin with albendazole appears safe, it offers no advantage over ivermectin alone in the control of onchocerciasis. The combination does not require an alteration in the dosage of either component.

Administration, Oral↗
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↗
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↗
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↗
PubMed2003

Immunopathogenesis of Onchocerca volvulus keratitis (river blindness): a novel role for TLR4 and endosymbiotic Wolbachia bacteria.

Infection with the parasitic nematode Onchocerca volvulus is associated with inflammation of the skin and cornea that can lead to blindness. Corneal damage is thought to occur as a result of the host inflammatory responses to degenerating microfilariae in the eye. We have utilized a murine model of corneal inflammation (keratitis) to investigate the immune and inflammatory responses associated with river blindness. Soluble extracts of O. volvulus, a filarial species that contains the endosymbiont bacteria Wolbachia or Acanthocheilonema viteae (a nematode not naturally infected with the bacteria) were injected into mouse corneas. Inflammatory responses and corneal changes were measured. We demonstrated a major role for endosymbiont Wolbachia bacteria and Toll-like receptor 4 (TLR4) in the pathogenesis of ocular onchocerciasis.

Animals↗
PubMed1997

Olecranon lesions caused by Onchocerca skrjabini in wild Japanese serows (Capricornis crispus).

Wild Japanese serows (Capricornis crispus) were found to have parasitic lesions in tendons that attached the musculus tricepus brachii to the olecranon. Histopathological study of the lesions showed chronic tendinitis with multiple granulation nodules around the worms. The lesions were found in 138 of the 353 serows examined and were more frequent in aged animals than young ones. Transverse ridges on the cuticle of the female midbody, the sizes and morphological features of the spicules, and the arrangement of the caudal papillae of the males showed the parasite to be Onchocerca skrjabini. Therefore, O. skrjabini causes olecranon lesions in addition to fibrous bursa formation in carpal and tarsal regions of the Japanese serows.

Aging↗
PubMed2025

Genetic structuring and estimation of reproductive adults in Onchocerca volvulus: A genome-wide analysis across hosts and regions.

Genomic analysis of parasites can deepen our understanding of their transmission, population structure, and important biological characteristics. Onchocerciasis (river blindness), caused by the parasitic nematode Onchocerca volvulus, involves adult worms residing in subcutaneous nodules that produce larval-stage microfilariae (mf), which are routinely detected in the skin for diagnosis. Whole-genome studies of mf are limited; most analyses have focused on the mitochondrial genome. We conducted a genome-wide analysis with 94% median nuclear genome coverage, analyzing 171, 37, and 98 mf from 16, 3, and 5 individuals from Ghana, Liberia, and the Democratic Republic of Congo, respectively. These data were used to investigate population differentiation, estimate the number of reproductive adult worms, and analyze genetic variation across chromosomes. Population genetic analyses across hosts and countries showed that nuclear genome diversity can reveal fine-scale genetic structure, even between geographically close countries, providing more resolution than mitochondrial haplotype data. By reconstructing maternal and paternal sibships, we estimated the number of reproductively active adult filariae. Comparisons between adult worm estimates from genetic data and nodule observations showed that genetics-based estimates were higher or equal to observed worm counts in 8 out of 9 hosts for female worms and 7 out of 9 hosts for male worms. Our analysis also revealed lower-than-expected X chromosome diversity, consistent with neo-X chromosome fusions in filarial species. This study represents an important step in using nuclear genome data from mf to support onchocerciasis elimination efforts and in developing genetic tools that could inform mass drug administration programs.

Onchocerca volvulus↗
PubMed2003

The activator-binding site of Onchocerca volvulus S-adenosylmethionine decarboxylase, a potential drug target.

S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in polyamine biosynthesis. In many eukaryotes its activity is stimulated specifically by putrescine. The AdoMetDC of the filarial parasite Onchocerca volvulus, however, is not only stimulated by putrescine but also by the naturally occuring polyamines spermidine and spermine. Several diamines, acetylated polyamines and polyamine analogues were used to analyse what molecular prerequisites are needed to stimulate nematode AdoMetDC activity. In the absence of an activator, the O. volvulus enzyme exhibits an extremely low specific activity. This fact, together with the unspecificity of activator binding, was thought to be useful for a new strategy to inhibit nematode AdoMetDC activity. Therefore, different polyamine analogues were tested as competitive inhibitors towards the stimulatory effect putrescine has on the O. volvulus and, in comparison, on the Caenorhabditis elegans and human AdoMetDC. Bis(aralkyl)- and bis(alkyl)-substituted polyamine analogues with a 3-7-3 backbone were found to inhibit AdoMetDC activities, however, probably without interfering with the putrescine stimulation. The best inhibitor, BW-1, was about 10-fold more effective against O. volvulus AdoMetDC than against the human enzyme. Unexpectedly, BW-1 was determined to be a competitive inhibitor with respect to AdoMet, having a Ki value of 310 microM for the putrescine-stimulated human AdoMetDC. Furthermore, we show for the O. volvulus and the human enzyme that the degree of inhibition by BW-1 depends on the actual putrescine concentration.

Adenosylmethionine Decarboxylase↗
PubMedDate not supplied

Macrofilaricidal effects of chloroquine on adult Onchocerca volvulus by local infiltration of palpable onchocercal nodules.

The macrofilaricidal effects of local infiltration of high concentrations of chloroquine into the capsule of onchocercal nodules on adult worms of Onchocerca volvulus was determined. Six weeks post infiltration, histological examination of single nodules showed all adult worms to be dead. With nodule conglomerates, there was localized action of chloroquine only on the adult worms in the infiltrated nodule, with no diffusion of the drug to adjacent nodules. Chloroquine infiltration of young, recently formed nodules to reduce the adult worm load of infected individuals may be an alternative method to costly nodulectomy.

Adult↗
PubMed2004

Uptake of Onchocerca volvulus (Nematoda: Onchocercidae) by Simulium (Diptera: Simuliidae) is not strongly dependent on the density of skin microfilariae in the human host.

The relation between the number of microfilariae (mf) ingested by host-seeking vectors of human onchocerciasis and skin mf load is an important component of the population biology of Onchocerca volvulus, with implications for disease control and evaluation of the risk of transmission recrudescence. The microsimulation model ONCHOSIM has been used to assess such risk in the area of the Onchocerciasis Control Program (OCP) in West Africa, based on a strongly nonlinear relation between vector mf uptake and human mf skin density previously published. However, observed levels of recrudescence have exceeded predictions, warranting a recalibration of the model. To this end, we present the results of a series of fly-feeding experiments carried out in savanna and forest localities of West Africa. Flies belonging to Simulium damnosum s.s., S. sirbanum, S. soubrense, and S. leonense were fed on mf carriers and dissected to assess the number of ingested mf escaping imprisonment by the peritrophic matrix (the number of exo-peritrophic mf), a predictor of infective larval output. The method of instrumental variables was used to obtain (nearly) unbiased estimates of the parameters of interest, taking into account error in the measurement of skin mf density. This error is often neglected in these types of studies, making it difficult to ascertain the degree of density-dependence truly present in the relation between mf uptake and skin load. We conclude that this relation is weakly (yet significantly) nonlinear in savanna settings but indistinguishable from linearity in forest vectors. Exo-peritrophic mf uptake does not account for most of the density dependence in the transmission dynamics of the parasite as previously thought. The number of exo-mf in forest simuliids is at least five times higher than in the savanna vectors. Parasite abundance in human onchocerciasis is regulated by poorly known mechanisms operating mainly on other stages of the lifecycle.

Africa, Western↗
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↗
PubMed1994

Phosphoprotein patterns in Onchocerca volvulus developmental stages.

Living females and microfilariae of Onchocerca volvulus incubated in culture medium containing [32P]orthophosphate were observed to phosphorylate their proteins rapidly. Patterns of phosphoproteins in extracts from these labelled parasites were compared after two dimensional electrophoresis and autoradiography. Protein extracts from eggs, microfilariae and adult females of O. volvulus were phosphorylated in the presence of [gamma-32P]ATP, magnesium acetate, and added cyclic AMP-dependent protein kinase or the endogenous protein kinase present in the extracts. Patterns of phosphoproteins were compared after separation by single and two-dimensional gel electrophoresis followed by autoradiography. Common phosphopeptide bands were observed when phosphorylated extracts from adult females, microfilariae and eggs were compared. However, extracts from eggs displayed unique phosphorylated polypeptides of M(r) 30,000 and 34,000 that were absent from the extracts from microfilariae. Furthermore, two phosphorylated polypeptides of M(r) 47,000 and 76,000 were detected in extracts from microfilariae but not from eggs. These results indicate that O. volvulus parasites may phosphorylate different proteins at different stages of their development.

Animals↗
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↗
PubMed2007

Innate immune responses to endosymbiotic Wolbachia bacteria in Brugia malayi and Onchocerca volvulus are dependent on TLR2, TLR6, MyD88, and Mal, but not TLR4, TRIF, or TRAM.

The discovery that endosymbiotic Wolbachia bacteria play an important role in the pathophysiology of diseases caused by filarial nematodes, including lymphatic filariasis and onchocerciasis (river blindness) has transformed our approach to these disabling diseases. Because these parasites infect hundreds of millions of individuals worldwide, understanding host factors involved in the pathogenesis of filarial-induced diseases is paramount. However, the role of early innate responses to filarial and Wolbachia ligands in the development of filarial diseases has not been fully elucidated. To determine the role of TLRs, we used cell lines transfected with human TLRs and macrophages from TLR and adaptor molecule-deficient mice and evaluated macrophage recruitment in vivo. Extracts of Brugia malayi and Onchocerca volvulus, which contain Wolbachia, directly stimulated human embryonic kidney cells expressing TLR2, but not TLR3 or TLR4. Wolbachia containing filarial extracts stimulated cytokine production in macrophages from C57BL/6 and TLR4(-/-) mice, but not from TLR2(-/-) or TLR6(-/-) mice. Similarly, macrophages from mice deficient in adaptor molecules Toll/IL-1R domain-containing adaptor-inducing IFN-beta and Toll/IL-1R domain-containing adaptor-inducing IFN-beta-related adaptor molecule produced equivalent cytokines as wild-type cells, whereas responses were absent in macrophages from MyD88(-/-) and Toll/IL-1R domain-containing adaptor protein (TIRAP)/MyD88 adaptor-like (Mal) deficient mice. Isolated Wolbachia bacteria demonstrated similar TLR and adaptor molecule requirements. In vivo, macrophage migration to the cornea in response to filarial extracts containing Wolbachia was dependent on TLR2 but not TLR4. These results establish that the innate inflammatory pathways activated by endosymbiotic Wolbachia in B. malayi and O. volvulus filaria are dependent on TLR2-TLR6 interactions and are mediated by adaptor molecules MyD88 and TIRAP/Mal.

Adaptor Proteins, Vesicular Transport↗
PubMed1977

Intracytoplasmic bacteria in Onchocerca volvulus.

Ultrastructural studies on Onchocerca volvulus disclosed intracellular organisms within the lateral chords of adult worms and of the larval stages. In the females the organisms were also present in the oogonia, oocytes, developing eggs and microfilariae. The organisms, found within vesicles of host (filarid) membrane and limited to the cytoplasm of infected cells, appeared to have a developmental cycle consisting of three morphologically distinct forms: a small spheroidal form up to 0.3 micronm in size, a bacillary form up to 1.5 micron7 in length and 0.7 micronm in diameter, and a third form, intermediate in size between the former and the latter, characterized by a dense inclusion. The intravesicular location and the developmental cycle consisting of three distinct forms are the two characteristics which suggest that these organisms are more similar to the chlamydiae than to the rickettsiae, in spite of their being transovarially transmitted. The significance of these findings with respect to the host-parasite relationship and pathogenesis of onchocerciasis is presently unknown and will require further study.

Animals↗
PubMed1977

Post-prandial transportation and maintenance of Simulium ochraceum infected with Onchocerca volvulus.

Simulium ochraceum females collected after feeding on subjects harboring Onchocerca volvulus were maintained and transported from Guatemala to California in small plastic tubes. Each tube had a perforated cap for entry of air, a wick as a reservoir for the nutrient solution (30% sucrose), a strip of filter paper for anchorage, and contained one fly. The tubes were kept in plastic boxes which, in turn, were maintained in portable coolers. Direct sunlight, heat and mechanical trauma easily killed the flies; moreover, loss of flies was also due to oversaturated wicks, high humidity in the plastic boxes, and loose tube caps. Approximately 70% of the captured flies could survive an 8-day period of captivity, and approximately 40% were still alive 11 days after capture.

Animals↗