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PubMed2001

A stress-responsive glyoxalase I from the parasitic nematode Onchocerca volvulus.

Glyoxal, methylglyoxal and other physiological alpha-oxoaldehydes are formed by the lipid peroxidation, glycation and degradation of glycolytic intermediates. They are detoxified enzymically by the glyoxalase system. To investigate the physiological function of glyoxalase I in parasitic organisms, the cDNA for glyoxalase I from the filarial nematode Onchocerca volvulus (designated Ov-GloI) has been cloned and characterized. The isolated cDNA contains an open reading frame of 579 bp encoding a protein with a calculated molecular mass of 21930 Da. Owing to the high degree of sequence identity (60%) with human glyoxalase I, for which the X-ray structure is available, it has been possible to build a three-dimensional model of Ov-GloI. The modelled core of Ov-GloI is conserved compared with the human glyoxalase I; however, there are critical differences in the residues lining the hydrophobic substrate-binding pocket of Ov-GloI. A 22 kDa protein was obtained by heterologous expression in Escherichia coli. A homogeneous enzyme preparation was obtained by affinity purification and functional characterization of the recombinant enzyme included the determination of kinetic constants for methylglyoxal and phenylglyoxal as well as inhibition studies. Gel filtration demonstrated a dimeric structure. To assess the role of Ov-GloI as a potential vaccine candidate or serodiagnostic tool, the serological reactivity of the recombinant Ov-GloI was analysed with sera from microfilaria carriers and specific IgG1 antibodies were detected. The effects of oxidative insult, namely plumbagin and xanthine/xanthine oxidase, on the gene transcript level of Ov-GloI were investigated. By using a semi-quantitative PCR ELISA it was shown that Ov-GloI is expressed at elevated levels under conditions of oxidative stress.

Amino Acid Sequence↗

PubMed1991

Development of Onchocerca volvulus microfilariae injected into Simulium species from Cameroon.

Microfilariae (mff) of the savanna and forest strains of Onchocerca volvulus (Leuckart) were injected intrathoracically into adult females of Simulium damnosum Theobald sensu stricto, S.sirbanum Vajime & Dunbar, S.squamosum Enderlein and S.mengense Vajime & Dunbar. Nine days post infection (pi) 27-29% of the savanna mff and 31-38% of the forest strain had developed to third-stage larvae (L3), irrespective of the fly species, size or injection dose (5, 10 or 15 mff). Savanna flies supported the development of forest O.volvulus better than forest flies, in contrast to the results after per os infections. Therefore, in these four species of the S.damnosum complex from Cameroon, the peritrophic membrane is considered to be the main factor limiting the success rate of microfilarial development following the ingestion of blood infections, while the fly's haemolymph and intracellular environment play minor roles.

Animals↗

PubMed1990

Novel Onchocerca volvulus filaricides from Carapa procera, Polyalthia suaveolens and Pachypodanthium staudtii.

Suitable drugs for the elimination of adult Onchocerca volvulus are still needed since ivermectin, the new microfilaricide, appears to be ineffective against this parasite stage. Herein we report on the identification of filaricides in three medicinal plants. The compounds carapolide A, mexicanolide-methylangolensate mixture from Carapa procera and oliverine from Polyalthia suaveolens or Pachypodanthium staudtii when tested at 10-100 micrograms.ml-1 were found to exhibit considerable microfilaricidal activity after 24 hours of incubation. Oliverine was found to be filaricidal when tested against adult female worms at 100 micrograms.ml-1. Preliminary toxicity studies in mice showed carapolide A and the mexicanolide-methylangolensate mixture to be relatively non-toxic, whereas, oliverine had a minimal lethal dose of 8 mg.Kg-1 of body weight. Based on the above results further pharmacologic studies are recommended to determine, the potential application of the active compounds on the treatment of onchocerciasis.

Animals↗

PubMed2000

Immunity to onchocerciasis: cells from putatively immune individuals produce enhanced levels of interleukin-5, gamma interferon, and granulocyte-macrophage colony-stimulating factor in response to Onchocerca volvulus larval and male worm antigens.

Antigen-specific interleukin-5 (IL-5), gamma interferon (IFN-gamma), and granulocyte-macrophage colony-stimulating factor (GM-CSF) responses in individuals living in an area of hyperendemicity for onchocerciasis in Cameroon were examined. The responses against antigens prepared from Onchocerca volvulus third-stage larvae (L3), molting L3 (mL3), and crude extract from adult males (M-OvAg) were compared to the responses against antigens from adult female worms and skin microfilariae. Cytokine responses for the putatively immune individuals (PI) and the infected individuals (INF) were compared. A differential cytokine profile of IL-5 (Th2 phenotype) and IFN-gamma (Th1 phenotype) was found in these individuals in response to the antigens. In both the PI and the INF, Th2 responses against all the antigens tested were dominant. However, in the PI group as a whole, there was an enhanced Th2 response against the larval antigens and the adult male and adult female antigens, and a Th1 response in a subgroup of the PI (27 to 54.5%) against L3, mL3, and M-OvAg antigens was present. While the PI produced significantly higher levels of GM-CSF against L3, mL3, and M-OvAg antigens than the INF, there was no difference in the GM-CSF responses of the groups against the other antigens. The present study indicated that, in comparison to the INF, the PI have distinct larva-specific and adult male-specific cytokine responses, thus supporting the premise that immunological studies of the PI would lead to the identification of immune mechanisms and the target genes that play a role in protective immunity.

Animals↗

PubMedDate not supplied

Demonstration of immunoglobulin G antibodies against Onchocerca volvulus excretory-secretory antigens in different forms and stages of onchocerciasis.

The excretory-secretory (E-S) products of helminths are considered to comprise immunogenic molecules of high diagnostic value. In the present study, the serodiagnostic potential of the E-S products released in vitro by cultured female Onchocerca volvulus was investigated by enzyme-linked immunosorbent assay (ELISA) and Western blotting using 190 serum samples from persons infected with O. volvulus and unexposed persons. The sensitivity of detection of anti-O. volvulus E-S antibodies was 94% for sera from patients with the generalized form of onchocerciasis and 100% for sera from patients with the chronic hyperreactive form (sowda). 95% of the sera from amicrofilaridermic persons, who subsequently became microfilaridermic within 2 years, reacted with O. volvulus E-S antigens and the donors were therefore regarded as having had a prepatent infection when first examined. These sera gave higher (P < 0.05) ELISA optical densities than sera from the same persons obtained when they had become patent, indicating a loss of antibody reactivity after emergence of microfilariae. The specificity of the E-S ELISA was 100% when sera of subjects infected with Wuchereria bancrofti were used, and at least 88% for Mansonella perstans sera. In Western blot analysis, the sera of persons with generalized onchocerciasis recognized 7 protein bands. Many E-S proteins were stained less intensely by the sera of subjects with generalized onchocerciasis than by the sera of sowda patients. Similar antigen bands were demonstrated using sera from the persons with prepatent infections.

Animals↗

PubMed2005

Case report and brief commentary: Wuchereria bancrofti and Onchocerca volvulus co-infection in a refugee from Sierra Leone.

Filarial infection is endemic in the tropics and is a public health problem in Africa, Asia, South and Central America, and the Pacific Islands. Co-infection with filarial nematodes, if unrecognized, can result in untoward therapeutic consequences. We report a case of co-infection of Wuchereria bancrofti and Onchocerca volvulus that was diagnosed by direct blood smear (W. bancrofti ) and serology (O. volvulus) in a native of Sierra Leone. We comment briefly on the therapeutic implications of the co-infection.

Adult↗

PubMed1986

Phosphoenolpyruvate carboxykinase from Onchocerca volvulus and O. gibsoni.

Phosphoenolpyruvate carboxykinase, a rate-limiting enzyme at the branchpoint of phosphoenolpyruvate (PEP), was demonstrated in Onchocerca volvulus and O. gibsoni. The activity of PEP-carboxykinase from both filarial worms depends absolutely on the presence of divalent cations; in addition to Mg2+ the enzyme activity was strongly activated by Mn2+. The Michaelis constants for PEP, GDP and KHCO3 of the PEP-carboxykinase from O. volvulus were determined to be 0.16 mM, 0.15 mM and 20 mM, respectively; those of the enzyme from O. gibsoni were 0.16 mM, 0.13 mM and 12 mM. Quinolinate was found to be a potent inhibitor of the enzyme from both filarial worms. The inhibition constants were determined to be 11 microM and 15 microM for the enzyme from O. volvulus and O. gibsoni. It is suggested that the activity of PEP-carboxykinase, the initial enzyme of the alternate route from PEP to succinate, may be regulated by ATP-levels. The inhibition constants for ATP were determined to be 0.26 mM and 0.13 mM for the enzyme from O. volvulus and O. gibsoni.

Adenosine Triphosphate↗

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↗

PubMed1998

Mast cell distribution in nodules of Onchocerca volvulus from untreated patients with generalized onchocerciasis.

Onchocercomata with a defined worm population were analysed to elucidate the distribution of mast cells. Nodules with live females were classified according to the presence or absence of microfilariae. Immunohistochemical staining was performed using antibodies specific for mast cells or IgE. Mast cells appeared singly or in diffuse accumulations perivascularly and in inflammatory infiltrates between adult Onchocerca volvulus and in the capsular area. No mast cells were detected in cystic parts. Only few, scattered mast cells were found in the fibrous zone around the adult worm. They were increased with stronger infiltration and hence, related to the inflammatory cells. Mast cells were never localized directly at adult worms or microfilariae. A correlation of the mast cell distribution to the occurrence of eosinophils was observed regarding higher numbers of mast cells and eosinophils in nodules with microfilariae-producing females. Nodules with single males revealed higher numbers of mast cells than nodules with non-producing females, although both contained very few eosinophils. Onchocercomata with dead worms contained significantly more mast cells than those with live filariae. In conclusion, the localization and frequency of mast cells is contingent on the vitality and productivity of the worms and therefore, indirectly and directly on the release of O. volvulus antigens.

Africa↗

PubMed2000

DNA immunization with Onchocerca volvulus genes, Ov-tmy-1 and OvB20: serological and parasitological outcomes following intramuscular or GeneGun delivery in a mouse model of onchocerciasis.

The objective of this study was to evaluate whether the distinct immune responses invoked by epidermal and intramuscular DNA immunization could be harnessed to improve upon the levels of protection to Onchocerca volvulus infective larvae achieved previously by recombinant protein immunization. Intramuscular (IM) and epidermal (GeneGun) routes of DNA immunization generally drive T helper1 and Th2 dominant responses, respectively. This dichotomy was used in an attempt to further define the nature of host-protective immunity in a mouse model of onchocerciasis. Mice were immunized with DNA plasmids expressing the O. volvulus antigens, Ov-TMY-1 (tropomyosin) and OvB20 (a nematode specific gene product). While, IM and GeneGun immunization of mice with Ov-tmy-1 induced expected Th1/Th2-associated IgG isotype profiles, mice responded to OvB20 immunization with a Th2 dominant response, irrespective of the delivery route. Despite inducing potent serological responses, neither DNA construct promoted statistically significant levels of protection to L3 challenge infection. We conclude that DNA immunization has good potential for induction of humoral responses against nematode infections and that serological responses alone do not predict vaccination efficacy under the conditions used here to measure host resistance to parasite challenge.

Animals↗

PubMed1997

Differential immune response to Onchocerca volvulus: IgG4 antibody responses differ in onchocerciasis patients from Guatemala and Ghana.

Geographical differences exist in the clinical features of onchocerciasis in Central America and West Africa, which could be due in part from variations in the antigenic composition of the infecting organism. In an attempt to address this question, adult female worms of Onchocerca volvulus derived from nodules of patients from Guatemala and Ghana were compared in terms of polypeptide composition and the IgG4 antibody responses induced in patients. It was shown that a Tris-buffer soluble extract from the worms obtained in the two regions differ in polypeptide composition. Furthermore, the diagnostic polypeptides were found to be in the 30 kDa region but the recognition of these antigens was less intense and less frequently observed in the sera of microfilaria (mf) positive patients from Ghana than equivalent age and sex matched patients from Guatemala.

Adolescent↗

PubMed2002

DNA-based detection of onchocerca volvulus.

During the 1980s, the idea of using deoxyribonucleic acid probes for specific identification and diagnosis of infectious agents became very fashionable. There was therefore an explosion in the development of these tools and one particular group of organisms which received much attention was the parasitic nematodes. This review traces the development and use of such probes with the filarial nematode Onchocerca volvulus, with emphasis on their application to resolving certain 'problems' associated with this parasite, e.g. whether or not strains exist and difficulties in distinguishing the infective larval stage morphologically from related species.

Animals↗

PubMed1994

[ Onchocerciasis control program in West Africa: socioeconomic development and risk of recrudescence of transmission. 1. Experimental study of the transmission of Onchocerca volvulus strains from Southwestern Sierra Leone by Simulium sirbanum].

As part of the return of savanna migrants installed since a long time in forest regions, in the south of Sierra Leone, we carried out an experimental study about a cross-transmission between Simulium sirbanum from Missira (West-Mali) and the forest strain of Onchocerca volvulus in the south-west of Sierra Leone. This study will allow to know if there is a risk of onchocerciasis transmission recrudescence in relation to the reinstallation of these migrants in their native region. Because of the very high limitation to the forest strain of O. volvulus microfilariae output of the peritrophic membrane reduction with savanna black-flies and according to the very low mature parasite out put of S. sirbanum with this strain observed along this experimentation, the forest strain of O. volvulus from the south Sierra Leone appears maladjusted to S. sirbanum, the main vector of onchocerciasis in savanna regions. This observation implicates a very low intensity of transmission for this forest strain by savanna onchocerciasis vectors. The return of savanna migrants in their native region, installed in the south Sierra Leone since several decades, could not be, in a short time, an origin of onchocerciasis recrudescence in savanna regions of the Onchocerciasis Control Programme area cleaned by an effective vector control carried out since 1975 sustained now by a chemotherapeutic treatment reducing the human parasite reservoir. However, the preservation of this acquired necessitates an epidemiological supervision increased, because the interactions between the vector and the parasite for a long time could carry away a mutual adaptation and a sickness recrudescence.

Animals↗

PubMed2003

Cloning and biochemical characterization of blisterase, a subtilisin-like convertase from the filarial parasite, Onchocerca volvulus.

Blisterase is a subtilisin-like proprotein convertase of nematodes. The enzyme is named after the blistered cuticle found in Caenorhabditis elegans with the bli-4 e937 mutation. The critical role of the enzyme in cuticle production makes it a potential drug target for parasitic nematodes. We have cloned and expressed blisterase from the parasitic nematode Onchocerca volvulus, a major cause of blindness in Africa. The catalytic domain of the protease exhibits 84% identity with the corresponding domain of its closest homologue, C. elegans blisterase. O. volvulus blisterase expressed in insect cells has maximal activity in 1 mm calcium at neutral pH. The protease is inhibited by EDTA, the suicide substrate decanoyl-RVKR-chloromethylketone, alpha1-antitrypsin Portland and by its own propeptide. Substrate assays with fluorescent peptides show that O. volvulus blisterase requires a P4 arginine and a basic amino acid at P1 for cleavage. The kcat of blisterase on the peptide substrate, t-butyloxycarbonyl-RVRR-4-methylcoumaryl-7-amide was determined to be 0.018 s-1. In vitro cleavage studies with the nematode polyprotein antigen demonstrated that blisterase cleaved at tetrabasic (RRKR) but not at dibasic (KR) sites. This report describes the first biochemical characterization of the nematode specific protease, blisterase.

Amino Acid Chloromethyl Ketones↗

PubMed1985

Parasite-specific inhibition of 5'-nucleotidase from Onchocerca volvulus and Dirofilaria immitis by the amoscanate-derivative CGP 8065.

The presence of 5'-nucleotidase was demonstrated in Onchocerca volvulus and Dirofilaria immitis; the bulk of activity was found in the particulate fraction. The enzyme of filarial worms exhibited a broad pH-optimum between 6.4 and 8.0 and substrate specificity for nucleotides compared to glucose-6-phosphate and p-nitrophenyl phosphate. The apparent Km-values for AMP were found to be 0.15 mM and 0.22 mM for the enzyme from O. volvulus and D. immitis, respectively. The activity of 5'-nucleotidase from both filarial worms was effectively inhibited by the filaricidal compound CGP 8065, a dithiocarbamate-derivative of amoscanate, whereas the 5'-nucleotidase from rat liver was not affected. The parasite-specific inhibition by CGP 8065 was found to be reversible and to be competitive with respect to the substrate AMP. The inhibition constants were calculated to be 24 microM and 8 microM for the enzyme from O. volvulus and D. immitis, respectively.

5'-Nucleotidase↗

PubMed2003

Isolation and characterization of the regulatory subunit of cAMP-dependent protein kinase from the filarial parasite Onchocerca volvulus.

Protein kinases exert major regulatory effects in eukaryotic signaling events. As these proteins play central regulatory and sensory functions they are interesting targets for antiparasitic drug development and serve as vaccine candidates. A cDNA with an open reading frame of 1122 bp coding for the regulatory subunit of the cAMP-dependent protein kinase (Ov-pka-r) of the pathogenic human nematode Onchocerca volvulus has been isolated. The predicted protein displays 84% homology to the corresponding protein of Caenorhabditis elegans and 71% to the human homologue. The O. volvulus protein has unique features, it includes six cysteine residues, as compared to four residues in mammals. Ov-PKA-r was recombinantly expressed as His-tagged protein and under reducing conditions showed a molecular mass of 52 kDa. In sera from O. volvulus patients IgG antibodies were found that strongly reacted with the recombinant Ov-PKA-r. Using rabbit antisera raised against the recombinant protein for immunohistology allowed the localization of the native Ov-PKA-r within the nervous system and sensory organs of adult O. volvulus worms and of microfilariae. The predominant expression in the nervous system and sensory organs as well as the unique structural features identify this signaling molecule of O. volvulus as a new and interesting target for drug or vaccine development.

Amino Acid Sequence↗

PubMed1993

Identification of a zinc finger encoding gene in Onchocerca volvulus.

Eukaryotic transcription factors can be identified and classified according to conserved DNA-binding motifs and conserved regulatory domains. The functional and structural analysis, and the conservation of these genes among metazoans emphasizes the importance of these DNA-binding proteins in development and differentiation. In order to identify genes with common DNA-binding motifs in the genome of Onchocerca volvulus we have cloned a zinc finger encoding gene of the structure C2-H2. Using the Caenorhabditis elegans sex determining tra-1 gene as a probe we have identified two tra-1 related genes in the genome of O. volvulus. The zinc finger region of one of these genes (OvZf1) was subcloned and sequenced. The predicted protein has at least eight consecutive zinc fingers and each finger possesses the characteristic paired cysteine- and histidine residues and the proper spacing of the amino acids between the conserved residues.

Amino Acid Sequence↗

PubMed2001

The prevalence, intensity and clinical manifestations of Onchocerca volvulus infection in Toro local government area of Bauchi State, Nigeria.

Between January and October 1994, a study of the prevalence, intensity and clinical manifestations of onchocerciasis in nine communities of Toro local government area of Bauchi State, Nigeria was undertaken using the skin-snip method. Of the 1117 inhabitants examined, 188 (16.8%) were positive for microfilariae of Onchocerca volvulus. The prevalence of onchocerciasis was significantly higher (P < 0.05) among males than females, in subjects 21 years of age and above than in those in the first two decades of life, in nomads, farmers, hunters and fishermen than smiths and traders. Intensity of infection was light, not exceeding a geometric mean of 5.3 microfilaria per 2 mm skin bite. Preponderance of positive cases below 20 years presented no chronic signs. Conversely, persons above 20 years had higher microfilaria counts which coincides with the period when most clinical signs manifest. Microfilarial-rate and -density in relation to age were closely associated (r = 0.75, P < 0.001). The need for a sustained mass distribution of Mectizan in these communities is highlighted.

Adolescent↗