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PubMed1998

Use of P-glycoprotein gene probes to investigate anthelmintic resistance in Haemonchus contortus and comparison with Onchocerca volvulus.

A P-glycoprotein gene probe from the sheep parasitic nematode Haemonchus contortus was developed and used to analyse restriction fragment length polymorphisms between susceptible isolates and isolates resistant to either benzimidazole; levamisole and benzimidazole; or benzimidazole, ivermectin and closantel. No polymorphism could be correlated with any of the different resistances. A P-glycoprotein gene probe was also isolated from the human nematode parasite Onchocerca volvulus and an Onchocerca-specific PCR was developed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Onchocerca volvulus keratitis (river blindness) is exacerbated in BALB/c IL-4 gene knockout mice.

To determine the outcome of Onchocerca volvulus keratitis in IL-4(-/-) BALB/c mice, animals were immunized subcutaneously and injected into the corneal stroma with soluble O. volvulus antigens. IL-4(-/-) BALB/c mice had a deviated cellular response, with decreased serum IgE and IgG1 and elevated IgG2a compared with control BALB/c mice. In marked contrast to control BALB/c, C57BL/6, and IL-4(-/-) C57BL/6 mice, IL-4(-/-) BALB/c mice developed severe corneal opacification and neovascularization that was associated with a pronounced neutrophil infiltrate to the corneal stroma. STAT-6(-/-) BALB/c mice had the same phenotype as IL-4(-/-) BALB/c mice, and complement depletion had no effect on the severity of O. volvulus keratitis in these mice. These findings indicate that on a BALB/c background, IL-4 has a critical role in regulating neutrophil recruitment to the cornea and development of O. volvulus keratitis.

Animals↗
PubMed1994

Cloning of a cDNA encoding a putative nicotinic acetylcholine receptor subunit of the human filarial parasite Onchocerca volvulus.

A partial cDNA clone encoding a putative nicotinic acetylcholine receptor (ACHR) subunit of the human filarial parasite, Onchocerca volvulus, has been isolated and sequenced. A truncated open reading frame of 1308 bp capable of encoding 436 amino acids with a calculated M(r) of 51,209 was identified. The absence of the double cysteine residues necessary for neurotransmitter binding indicates that the cloned ACHR is a non-alpha subunit.

Amino Acid Sequence↗
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↗
PubMed2002

Differential cytokine and antibody responses to adult and larval stages of Onchocerca volvulus consistent with the development of concomitant immunity.

The possibility of concomitant immunity and its potential mechanisms in Onchocerca volvulus infection were examined by analyzing cytokine and antibody responses to infective larval (third-stage larvae [L3] and molting L3 [mL3]), adult female worm (F-OvAg), and skin microfilaria (Smf) antigens in infected individuals in a region of hyperendemicity in Cameroon as a function of age. Peripheral blood mononuclear cell interleukin 5 (IL-5) responses to F-OvAg and Smf declined significantly with age (equivalent to years of exposure to O. volvulus). In contrast, IL-5 secretion in response to L3 and mL3 remained elevated with increasing age. Gamma interferon responses to L3, mL3, and F-OvAg were low or suppressed and unrelated to age, except for responses to Smf in older subjects. IL-10 levels were uniformly elevated, regardless of age, in response to L3, mL3, and F-OvAg but not to Smf, for which levels declined with age. A total of 49 to 60% of subjects had granulocyte-macrophage colony-stimulating factor responses to all O. volvulus antigens unrelated to age. Analysis of levels of stage-specific immunoglobulin G3 (IgG3) and IgE revealed a striking, age-dependent dissociation between antibody responses to larval antigens (L3 and a recombinant L3-specific protein, O. volvulus ALT-1) which were significantly increased or maintained with age and antibody responses to F-OvAg, which decreased. Levels of IgG1 to L3 and F-OvAg were elevated regardless of age, and levels of IgG4 increased significantly with age, although not to O. volvulus ALT-1, which may have unique L3-specific epitopes. Immunofluorescence staining of whole larvae showed that total anti-L3 immunoglobulin levels also increased with the age of the serum donor. The separate and distinct cytokine and antibody responses to adult and infective larval stages of O. volvulus which are age related are consistent with the acquisition of concomitant immunity in infected individuals.

Adolescent↗
PubMed1998

The peroxidoxin 2 protein of the human parasite Onchocerca volvulus: recombinant expression, immunolocalization, and demonstration of homologous molecules in other species.

The peroxidoxin protein of the filarial parasite Onchocerca volvulus (OvPXN-2) belongs to a group of highly conserved antioxidant molecules. For a more detailed characterization of this protein and for determination of its expression pattern the OvPXN-2 protein was recombinantly expressed as a His-tagged protein. Under reducing conditions the recombinant protein had an apparent molecular mass of 28 kDa. Considering the size of the His-tag and the FLAG epitope introduced to the recombinant protein, this size is in agreement with that of the native protein identified in O. volvulus extract. Antiserum raised against the recombinant protein was used for immunolocalization. In O. volvulus the antigen is predominantly expressed in the hypodermis and particularly the lateral and median chords show high levels of expression. The protein is also expressed strongly in the hypodermis of infective larvae and more weakly in microfilariae. Related cross-reacting proteins were detected in several Onchocerca species and other filariae. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis in combination with Western blotting revealed proteins with almost identical mobility in extracts prepared from O. ochengi, O. gibsoni, and Dirofilaria immitis.

Animals↗
PubMedDate not supplied

The effect of ivermectin treatment on the antibody response to antigens of Onchocerca volvulus.

The effect of the microfilaricidal drug ivermectin on the antibody response to a detergent extract of adult Onchocerca volvulus (OvAg) and a number of specific recombinant peptides was examined. Three of the peptides were combined in a serodiagnostic 'cocktail' and the effect of ivermectin on the diagnostic performance of this assay was assessed. Immunoglobulin (Ig) G1 serum levels in response to OvAg significantly decreased following ivermectin treatment. The antibody response to only one recombinant peptide (OvMBP29) was significantly affected, with IgG levels decreasing following treatment. Levels of total IgE increased following treatment. No correlation was observed between initial antibody level (or change in antibody level) and any adverse reaction to treatment. The serodiagnostic 'cocktail' was 100% sensitive before and after the use of ivermectin. A serodiagnostic assay using specific recombinant peptides can be used to evaluate infection in the absence of dermal microfilariae in areas where ivermectin is used.

Adolescent↗
PubMed2004

Polymerase chain reaction monitoring of transmission of Onchocerca volvulus in two endemic states in Mexico.

To investigate the impact of mass ivermectin treatments in Mexico on Onchocerca volvulus transmission, entomologic surveys were carried out in the two endemic states of Oaxaca and Chiapas. The data suggest that substantial progress towards the goal of elimination has been made. A comparison pre- and post-ivermectin data from a community in Southern Chiapas showed a 97% decrease in seasonal transmission potential, but some level of polymerase chain reaction positivity was still detectable. In other communities from northern Chiapas and Oaxaca where there are no baseline data, there was an absence or near absence of infective flies. Residual transmission was not evenly distributed because differences were seen in the infection and infective rates from different catch points. These findings suggest that while substantial progress towards elimination has been made in Mexico, it may be necessary to modify ivermectin distribution strategies to eliminate transmission in areas where transmission persists.

Animals↗
PubMed1995

Onchocerca volvulus: identification and characterization of an immunogenic eggshell protein (Oveg1).

A major antigen recognized by human sera in Onchocerca volvulus infections is a parasite eggshell protein. The cDNA clone for this antigen was isolated from a lambda gt11 O. volvulus cDNA library using antisera from patients with high microfilarial counts. Sequence analysis of the cDNA clone predicts a polyglutamine repeat near the 5' end of the cDNA, and a motif of four arginines near the 3' end, reminiscent of that found in many regulatory proteins. The cDNA was subcloned into a yeast expression vector and reagent quantities of recombinant antigen produced in Saccharomyces cerevisiae. Antisera produced to the recombinant purified protein localized the antigen to the eggshell of developing microfilariae within the adult female uterus. No other sites of Oveg1 expression were noted in adult worms, but labeling was seen in internal membrane structures of L3 larvae. Sera from infected chimps recognized Oveg1 only after infections became patent. Sera from infected humans showed reactivity to Oveg1 that varied from 39 to 95%, depending upon the geographic location.

Amino Acid Sequence↗
PubMed1997

Immunization with the cross-reactive antigens Ov39 from Onchocerca volvulus and hr44 from human retinal tissue induces ocular pathology and activates retinal microglia.

Antigen Ov39, derived from Onchocerca volvulus, cross-reacts on both the T and B cell level with a nonhomologous human retinal antigen, hr44. Lewis rats were immunized to investigate the potential of these antigens to induce eye disease. Histologic and immunohistologic examination of ocular tissues revealed pathologic changes as early as day 12, which included induction or up-regulation of class II and CD68-like antigen on perivascular cells, ramified retinal microglia, dendritiform cells of the iris epithelium, and ciliary epithelium and significant breakdown of anterior and posterior blood-ocular barriers. Extravascular immunoglobulin and staining for CD68-like antigen was detected in the optic nerve after immunization with Ov39. Unrelated structural abnormalities of retina and lens seen in 8% of eyes examined significantly predisposed eyes to the development of Ov39- or hr44-induced pathology. These findings suggest a role for cross-reactive immune responses in the development of ocular onchocerciasis.

Animals↗
PubMed2000

Humoral responses to a secretory Onchocerca volvulus protein: differences in the pattern of antibody isotypes to recombinant Ov20/OvS1 in generalized and hyperreactive onchocerciasis.

The Onchocerca volvulus secretory protein Ov20/OvS1 represents a dominant antigen expressed in the infective larvae, microfilariae and adult stages of the parasite. The humoral responses to this protein have not yet been analysed in the polar clinical and immunological forms of onchocerciasis. Analysis by ELISA of class and subclass antibodies to Ov20/OvS1 in persons with the generalized or the hyperreactive form of onchocerciasis revealed similar strong responses of IgG1, IgG4 and IgM antibody levels in both forms of onchocerciasis and significant differences were observed in the IgE and IgA antibody classes. Computation of the ratios of antibodies showed that persons with the generalized form exhibited significantly higher ratios of IgG4 to IgG1, IgG4 to IgE, and IgM to IgE than patients with the hyperreactive form. To investigate the isotype recognition of antigenic sites on Ov20/OvS1 protein, three recombinantly expressed fragments (F1-3) of Ov20/OvS1 were probed using sera which strongly reacted with intact recombinant Ov20/OvS1. Epitope(s) on F1 comprising amino acid residues 1-63 were significantly recognized by IgG1 and IgE, while IgM recognized epitopes on all three fragments. The strongest reaction of IgM occurred with epitope(s) formed by residues 108-171 (F3). In contrast, IgG4 type antibodies were not reactive with either of the three OvS1 fragments, but they reacted with intact Ov20/OvS1 protein. Generalized onchocerciasis, unable to eliminate microfilariae, and hyperreactive onchocerciasis, with a high potency to eliminate or to reduce parasite loads, can be distinguished by a distinct pattern of isotype responses to Ov20/OvS1.

Animals↗
PubMed1989

Onchocerca volvulus heat shock protein 70 is a major immunogen in amicrofilaremic individuals from a filariasis-endemic area.

Infestation with organisms causing lymphatic filariasis (i.e. Wuchereria bancrofti and Brugia malayi) results in a variety of clinical presentations. It is possible that some of the variation is due to differences in host response to parasite. To determine whether individuals who live in an endemic area but differ in their clinical manifestations respond to different filarial antigens, we screened Onchocerca volvulus expression libraries with sera from a number of individuals belonging to different clinical groups. The results of the study demonstrate that there are indeed differences in the recognition of three cloned filarial antigens and that this differential recognition is related to clinical symptomatology. The most striking finding is that an Onchocerca volvulus protein homologous to the 70 kDa Xenopus laevis heat shock protein is primarily recognized by individuals who are amicrofilaremic. Further analysis is required to determine whether these antigens play any role in the pathogenesis of filarial infection or have any potential value in protective immunity.

Adolescent↗
PubMed1997

Production of both IFN-gamma and IL-5 by Onchocerca volvulus S1 antigen-specific CD4+ T cells from putatively immune individuals.

Protective immunity to the parasitic nematode Onchocerca volvulus (Ov) appears to be directed against molecules of invading L3 larvae. In this study, the cellular immune reaction to such an Ov L3 protein (S1) which is protective in an animal model was analyzed using peripheral blood mononuclear cells (PBMC) of individuals from a hyperendemic area in West Africa who were exposed to Ov but remained free from disease ('putatively immune individuals'). Despite seronegativity of these individuals against S1, proliferation of PBMC was inducible, allowing generation of an S1-specific T cell line which produced IFN-gamma upon stimulation with both Ov lysate and S1. However, S1 induced significantly more IL-5 than Ov lysate. S1-specific, DQ6 (DQA1*0103/DQB1*0603)-restricted T cell clones were generated which reacted against synthetic peptides comprising amino acids 99-111 of S1. These clones, which are the first generated against a recombinant fllarial antigen, produced both IFN-gamma and IL-5 as well as little IL-4, suggestive of a Th0-like phenotype. In conclusion, in putative immunity, reactivity against a particular parasite protein can be detectable on the level of T but not B cells. Induction of both IFN-gamma and IL-5 by S1 suggests that it may trigger macrophage plus eosinophil dependent killing of L3 in vivo. The identification of a likely DQ6 (DQA1*0103/DQB1*0603)-restricted T cell epitope may be of more general relevance, given that allele combinations of DQ6, including DQA1*0103/DQB1*0603, are negatively associated with diabetes mellitus.

Amino Acid Sequence↗
PubMed1995

Onchocerca volvulus larval antigen, OvB20, induces partial protection in a rodent model of onchocerciasis.

OvB20 is an antigen of Onchocerca volvulus preferentially recognized by sera from cattle vaccinated with irradiated infective larvae of Onchocerca lienalis. Antibodies raised against the recombinant protein were used to characterize the expression of the native protein in different developmental stages of O. volvulus and the rodent filaria Acanthocheilonema viteae. In O. volvulus, antibodies reacted to a polypeptide of 42 kDa in microfilariae and with proteins of 52 and 65 kDa in third-stage larvae. No products were detected in adult stages. Immunogold electron microscopy localized the native protein to discrete patches of the hypodermis and cuticle of infective larvae. Characterization of a homologous protein in A. viteae confirmed the stage-specific expression in infective larvae of the 65-kDa protein, which was secreted during in vitro culture. Vaccination of rodents against A. viteae with a B20-maltose-binding-protein fusion protein resulted in a 49 to 60% reduction in adult worm recoveries with a corresponding 97% reduction in microfilaremia.

Animals↗
PubMed1994

IL-4- and IL-5-dependent protective immunity to Onchocerca volvulus infective larvae in BALB/cBYJ mice.

A significant reduction in challenge worm survival occurred when BALB/cBYJ mice were vaccinated against Onchocerca volvulus infective third stage larvae (L3) by using irradiated O. volvulus L3. Challenge infections consisted of L3 implanted in diffusion chambers, which were used as a means to contain, and thus efficiently recover, the larvae from the host. The goal of the present study was to describe the mechanism of immune-mediated killing of O. volvulus L3 in diffusion chambers in mice. Direct contact between host cells and parasites was required for killing of larvae in immunized hosts. To define the mechanism of immune-mediated killing in this system, the time of influx of cells and cytokines into the infection site was compared with the time challenge infections were killed. The only cell type that was found to increase in diffusion chambers in immunized mice was eosinophils; maximal levels of eosinophils were coincident with the time of parasite killing. IL-5 was found in diffusion chambers of immunized mice coincident with the time of parasite killing; IL-5 was not found in diffusion chambers recovered from control mice. Significant levels of IFN-gamma were absent in the diffusion chambers of both groups. Immunized mice were treated with mAb to eliminate IL-5 or IL-4 to assess the role these cytokines or their by-products play in larval killing. Elimination of either IL-5 or IL-4 significantly reduced the protective effects of vaccination against larval O. volvulus.

Animals↗
PubMed1995

Immunological studies on an Onchocerca volvulus intermediate-filament protein.

We report the complete sequence of the cDNA encoding an intermediate filament (IF) protein from Onchocerca volvulus. The OVIF cDNA encodes a protein of 613 amino acid residues, which has a predicted molecular weight of approximately 70 kD. The size of the protein encoded by the OVIF cDNA corresponds well with estimates obtained in Western blotting experiments, but these same experiments suggest that Onchocerca sp. may contain at least two IF proteins. To identify the domain(s) of the OVIF protein responsible for immunogenicity in human filariasis patients, fragments of the OVIF cDNA were subcloned into the appropriate pGEX vector and Western blots of the corresponding fusion proteins probed with human sera. Pooled sera from general onchocerciasis or Bancroftian filariasis patients reacted only with the C-terminal region of the OVIF protein, whereas sowda onchocerciasis sera reacted 1-2 orders of magnitude more strongly and with a number of other epitopes. Immunolocalization experiments implied that the OVIF protein is associated with both muscle and a number of specific membrane layers. These studies provide the basis for evaluation of the protective potential of the OVIF protein.

Amino Acid Sequence↗