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PubMed1998

In-vitro uptake of ivermectin by adult male Onchocerca ochengi.

Ivermectin is not lethal to the adult worms of Onchocerca volvulus or to those of O. ochengi, a cattle parasite closely related to O. volvulus. Although ivermectin penetrates the nodules in which the adults of these nematodes live, it is not known what levels of the drug enter the worms. Adult male O. ochengi were incubated in [3H]ivermectin in a saturated solution of unlabelled ivermectin (11.44 microM), to measure uptake by the oral and transcuticular routes, and in [3H]inulin, to ascertain if oral ingestion occurs in vitro. Uptake of [3H]ivermectin was high [1040 disintegrations/min (d.p.m.) at 3 h, representing a mean total of 86 pmoles ivermectin/worm] and occurred predominantly by the transcuticular route. Viability of worms was not reduced by this exposure, and uptake continued for up to 12 h. Only low levels of [3H]inulin (four d.p.m.) were detected in worms, indicating that the gut is probably not functional in vitro. Scanning and transmission electron microscopy revealed that the epicuticle of both sexes had an irregular surface which was pitted with a honeycomb structure in males, and rough and abundantly folded in females. These structures greatly increased the absorptive surface of the worms. In conclusion, ivermectin is able to enter adult O. ochengi males at concentrations sufficient to kill non-filarial nematodes.

Animals↗
PubMed1991

Immunological crossreactivity between a cloned antigen of Onchocerca volvulus and a component of the retinal pigment epithelium.

Onchocerciasis (river blindness) is a major blinding disease in Africa, Central America, and South America. Loss of vision can be due to corneal change, optic atrophy, or chorioretinal disease. It has been suggested that autoimmunological reactions resulting from crossreactivity between parasite antigens and components of eye tissues contribute to development of ocular pathology. Using sera collected from onchocerciasis patients as a screening reagent, a cDNA clone (Ov39) has been isolated from a lambda gt11 expression library of Onchocerca volvulus. This antigen exhibits immunological crossreactivity with a component of retinal pigment epithelium cells (RPE). Antiserum raised against this recombinant peptide immunoprecipitates a 22,000 Mr antigen of adult O. volvulus and recognizes a 44,000 Mr component of bovine RPE by Western blotting. A 44,000 Mr antigen of cultured human RPE metabolically labeled with 35S-methionine can be immunoprecipitated with the same antiserum. An antigen of the same size is recognized by a rabbit antiserum raised against whole O. volvulus extract. Immunocytochemical studies on cryostat sections of the bovine eye using the antirecombinant sera localizes this antigen to the RPE.

Amino Acid Sequence↗
PubMed1995

Molecular and immunological characterization of hr44, a human ocular component immunologically cross-reactive with antigen Ov39 of Onchocerca volvulus.

Structural similarities between host self-antigens and infectious organisms may be involved in the expression of autoimmune reactivity and development of autoimmune disease. The unique eye pathology associated with Onchocerca volvulus infection, particularly the development of posterior segment lesions, may be promoted by such autoreactive responses. Ov39 is a parasite-derived antigen that has been shown previously to be antigenically cross-reactive with a 44,000-M(r) host ocular component. A clone, designated hr44, was isolated from a cDNA library of human retina by immunoscreen using serum to Ov39. A monoclonal antibody raised to Ov39 also reacted with hr44 and gave evidence for a shared conformational epitope. The primary structure analysis showed that identities between the antigens are limited and confined to small peptides. The cross-reactivity between the antigens appears to involve T cells, since Ov39-specific T cells can be stimulated by hr44, a neural-specific antigen. Based on secondary structure prediction, hr44 has the typical features of a membrane-associated type I antigen with an amino-terminal extracellular domain. mAbs and antisera localized the antigen in the optic nerve, neural retina, retinal pigment epithelium, as well as the epithelial layers of ciliary body and iris.

Amino Acid Sequence↗
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↗
PubMed2001

Early human infection with Onchocerca volvulus is associated with an enhanced parasite-specific cellular immune response.

The immune response after early exposure to or infection with Onchocerca volvulus was investigated in an autochthonous focus caused by the migration of infected persons to a previously unaffected area in Ecuador. Peripheral blood mononuclear cell (PBMC) proliferative and cytokine responses (interferon [IFN]-gamma and interleukin [IL]-5) to filarial antigens were measured in 14 subjects with serologic evidence of exposure and in 7 subjects with evidence of dermal microfilarial DNA and were compared with responses in 43 subjects with chronic O. volvulus infections. PBMC proliferative and cytokine responses (IFN-gamma and IL-5) to parasite antigens were elevated in the early exposure/infection group, compared with those in the chronic infection group. Addition of an IL-10-neutralizing antibody to filaria antigen-stimulated cultures resulted in significantly elevated proliferative responses in the chronic infection group. The findings suggest that early exposure and early parasite patency are associated with a vigorous cellular response, but, as infections become chronic, the cellular response becomes down-regulated, partly through an IL-10-dependent mechanism.

Adolescent↗
PubMed2002

Onchocerca volvulus-exposed persons fail to produce interferon-gamma in response to O. volvulus antigen but mount proliferative responses with interleukin-5 and IL-13 production that decrease with increasing microfilarial density.

The cellular immune response to Onchocerca volvulus antigen (OvAg) was studied in 551 persons exposed to O. volvulus transmission in a hyperendemic area of Ghana, West Africa. A whole-blood assay showed that, in response to a soluble O. volvulus extract, cell proliferation, as well as interleukin (IL)-5 and IL-13 concentrations in the supernatants, were high in cultures of blood from microfilaria (mf)-negative persons and significantly decreased with increasing mf counts of the donors. Only background concentrations of interferon (IFN)-gamma were found, and these did not correlate with mf counts. In response to a mitogen, cells from all persons strongly reacted with proliferation and secretion of all 3 cytokines studied. These findings show that the response of human peripheral blood cells to OvAg does not include significant IFN-gamma production; that mf negativity is associated with IL-5 and IL-13 production but not, as previously suggested, with IFN-gamma production; and that IL-5 and IL-13 production decreases with increasing mf density.

Adolescent↗
PubMed2002

Onchocerca volvulus microfilariae avoid complement attack by direct binding of factor H.

The filarial parasite Onchocerca volvulus is the causative agent of river blindness. The adult worms produce microfilariae (mf), which are responsible for the disease pathogenesis; mf activate the complement system, but the activation stops before the formation of terminal complement complexes. Because of the arrest of complement activation, this study analyzed binding of the main alternative pathway regulator, factor H (fH), to the mf. The mf bound fH after incubation in nonimmune human serum or with purified radiolabeled fH. In the presence of factor I, mf-bound fH promoted the cleavage of complement 3 molecule b (C3b) to iC3b. An analysis with recombinant constructs of fH showed that the C-terminal short consensus repeats (SCRs) 8-20 of fH bound to mf, whereas the N-terminal SCRs 1-7 containing the complement-regulatory domains in SCRs 1-5 did not. Thus, mf of the nematode O. volvulus may evade human complement by binding fH and by promoting inactivation of C3b into iC3b.

Animals↗
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↗
PubMed1997

Differences in cytokine responses to Onchocerca volvulus extract and recombinant Ov33 and OvL3-1 proteins in exposed subjects with various parasitologic and clinical states.

Subjects with generalized onchocerciasis (GEN), with the sowdah form, and with exposure but without onchocerciasis (endemic normal/putatively immune; EN/PI) were studied for cytokine responses to Onchocerca volvulus extract (OvAg) and recombinant Ov33 and OvL3-1 proteins. Higher levels of cytokines were produced in response to OvAgs in sowdah and EN/PI than in GEN subjects. Peripheral blood mononuclear cells did not produce interferon-gamma in response to antigens. OvAg induced interleukin (IL)-5, IL-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), and soluble IL-2 receptor. EN/PI and sowdah persons produced significantly more IL-5 and IL-2 than GEN subjects, and EN/PI subjects had significantly higher GM-CSF levels than GEN persons. The low IL-5 and GM-CSF levels in GEN subjects were increased by addition of exogenous IL-2. Ov33 and OvL3-1 stimulated production of IL-10 and less IL-5 and IL-2. The study groups did not show a strict Th2-like cytokine response.

Animals↗
PubMedDate not supplied

Humoral and cellular immune responses to Onchocerca volvulus infection in humans.

Onchocerciasis is one of the major filarial diseases affecting humans and a leading cause of blindness. Control of the disease by chemotherapy and by elimination of the vector is not feasible in most areas of endemicity. The host immune response is thought to play a major role in the pathogenesis of complications. However, there is no clear evidence of protective immunity to reinfection in individuals who continue to be exposed to infective larvae. Antigens of Onchocerca volvulus are complex and show extensive cross-reactivity with other filarial parasites of humans and animals. Infection in humans results in the production of precipitating and reaginic antibodies to the parasite and in increases in levels of immunoglobulins that have no apparent specificity for parasitic antigens. Chronic antigenic stimulation in the presence of an antibody response leads to increased levels of circulating immune complexes. Cell-mediated immunity to parasite-derived antigens, as measured by migration inhibition, lymphocyte blastogenesis, and delayed skin-test reactivity, is decreased during infection. In addition, there is a decrease in delayed skin-test reactivity and in lymphocyte blastogenesis in response to unrelated antigens.

Antibody Formation↗
PubMedDate not supplied

Antigens of Onchocerca volvulus.

Most studies on immunologic responses to Onchocerca volvulus have employed extracts or antigens from related filarial parasites. Consequently, little is known about the nature of O. volvulus antigens. Potential antigen sources include in vitro cultures and physicochemical fractionation of O. volvulus extracts. IgE antibody responses to a wide range of antigens occur in patients with onchocerciasis, but there is little evidence of species specificity in serologic tests. Some potent allergens are released by microfilariae, but host serum proteins appear to contaminate the most reactive fractions obtained thus far. Antibody-mediated cell adherence to microfilariae of O. volvulus occurs in vitro, and both stage and species specificity have been demonstrated. Monoclonal antibodies to O. volvulus antigens have been prepared, but, unfortunately, all to date show cross-reactivity to antigens of other filarial nematodes. Circulating antigens have been detected in patients' sera; no data are available yet on the specificity of these components. Research needs include the need for species- and stage-specific reagents for immunodiagnostic assays and for investigations on immunopathogenic mechanisms in onchocercal disease.

Animals↗
PubMed1989

Onchocerca volvulus recombinant antigen: physical characterization and clinical correlates with serum reactivity.

An Onchocerca volvulus cDNA clone expressing epitopes found in adult and larval parasites, designated lambda RAL-2, was derived from a 1,000-base message present in adult O. volvulus, which encodes a protein with an apparent molecular weight of 17,000. This protein does not appear to be extensively posttranslationally modified. Serum samples from 52 individuals exposed to O. volvulus were examined for antibodies recognizing the lambda RAL-2 recombinant antigen; 77% produced such antibodies. In addition, individuals producing antibodies recognizing the recombinant antigen were significantly less likely to develop some aspects of ocular pathology associated with O. volvulus infection than were individuals who did not do so. These results suggest that recombinant antigens such as that produced by lambda RAL-2 may be useful in attempts to understand the mechanism of O. volvulus-induced ocular pathology.

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↗
PubMed1995

Immunity to onchocerciasis: putative immune persons produce a Th1-like response to Onchocerca volvulus.

Immunity to Onchocerca volvulus (Ov) infection is suggested by the presence of putatively immune (PI) subjects in a region of Ecuador in which Ov is endemic. PI subjects were identified by traditional diagnostic methods combined with a polymerase chain reaction-based assay for Ov DNA in skin snips. Responses of peripheral blood mononuclear cells (PBMC) from the PI group (n = 16) were compared with those of persons with active infection (microfiladermic [MF] subjects; n = 51). PBMC of PI subjects proliferated significantly more to Ov antigen (OvAg; P < .009) than did PBMC of MF persons but less to streptolysin-O (P < .001). Cytokine analysis of PBMC culture supernatants revealed that PI subjects (n = 11) produced significantly more interferon-gamma to OvAg than did those in the MF group (n = 18; P = .018), less interleukin (IL)-5 to nonparasite antigen (P = .003) and mitogen (P = .012), and less IL-10 spontaneously (P = .016). Thus, immunity to Ov may in part be mediated by an antigen-specific Th1-type response.

Adolescent↗
PubMed1995

Resistance to Onchocerca volvulus: differential cellular and humoral responses to a recombinant antigen, OvMBP20/11.

Persons putatively immune (PI) to Onchocerca volvulus (Ov) infection were identified in Ecuador on the basis of epidemiologic, clinical, and parasitologic findings. Immune responses of PI subjects to a recombinant onchocercal protein, OvMBP20/11, were determined and compared with those of a comparable infected (INF) group from the same Ov-endemic area. PI subjects had significantly less antibody reactivity to this molecule; however, not all INF subjects had an antibody response. IgG1 and IgG4 were the predominant IgG subclasses induced to this molecule, and the amount of IgG1 produced was the only significant difference between the PI and INF groups. In contrast to the antibody responses, proliferative responses to OvMBP20/11 were significantly higher in PI than in INF subjects. Cytokine analysis of peripheral blood mononuclear cell culture supernatants revealed that INF subjects produced significantly more interleukin-10 in response to OvMBP20/11 than did PI subjects. This antigen induced few other cytokines, and there were no differences between study groups.

Animals↗
PubMed1995

Determining the prevalence of Onchocerca volvulus infection in vector populations by polymerase chain reaction screening of pools of black flies.

An important variable in the epidemiology of arthropodborne diseases is the intensity of transmission, which is a function of host-vector contact and the prevalence of infection in the vector population. This latter value is often difficult to estimate. It is possible to envision the application of polymerase chain reaction (PCR) assays to this problem. To accomplish this, the assay must detect a single infected vector in a pool containing a large number of uninfected individuals. It must also be possible to calculate the prevalence of infection from the number of positive pools. A PCR assay for detecting Onchocerca volvulus in pools of vector black flies is described, and an algorithm is presented to calculate the prevalence of infection in the vector population, based upon the proportion of PCR-positive pools. This algorithm should be applicable to any disease for which a PCR assay is available.

Algorithms↗
PubMed1996

Polymerase chain reaction-based assessment after macrofilaricidal therapy in Onchocerca volvulus infection.

A recently developed polymerase chain reaction (PCR)-based assay is significantly more sensitive than current methods for diagnosing Onchocerca volvulus infection, and it overcomes many difficulties in identifying active onchocerciasis. Since chemotherapy is widely used to treat onchocerciasis, the utility of PCR in assessing responses to treatment and in predicting recrudescence is important. Twenty-eight patients who had skin snips positive for microfilariae (Mf) were studied 120 days after receiving amocarzine, when each was negative for Mf: 16 (57%) were positive for O. volvulus DNA in the PCR-based assay. Of these, 14 (88%) were Mf positive when reassessed parasitologically on day 240, and all were Mf positive on day 365. Equally important was the finding that 12 patients had cleared both Mf and Mf DNA; only 1 was Mf positive at day 240. This suggest that the PCR-based assay provides a sensitive means assessing infection status after macrofilaricidal chemotherapy and is an early predictor of persons likely to have a recurrence of Mf.

Animals↗
PubMed1996

Immunoregulation in onchocerciasis: persons with ocular inflammatory disease produce a Th2-like response to Onchocerca volvulus antigen.

To examine the role of specific cytokines in mediating the clinical manifestations of human onchocercal disease, microfilariae-positive Ghanaian subjects with inflammatory ocular disease were compared with microfilariae-positive subjects without ocular disease. Onchocerca volvulus antigen (OvAg)-stimulated peripheral blood mononuclear cells (PBMC) from subjects with disease produced significantly more interleukin (IL)-10 (with disease = 447.34 vs. without disease = 292.22 pg/mL; P < .01) and IL-5 (with disease = 33.36 vs. without disease = 27.26 pg/mL; P = .02). OvAg-stimulated IL-4 and interferon (IFN)-gamma levels were essentially undetectable in either group. When cytokine mRNA levels were measured by reverse transcriptase-polymerase chain reaction ELISA, persons with disease produced significantly more OvAg-stimulated IL-4, IL-5, and IL-10 mRNA (P = .03, < .01, .05, respectively). No difference in IFN-gamma mRNA production by either group was seen. Addition of neutralizing alpha IL-10 antibody to OvAg-stimulated PBMC increased TFN-gamma production to detectable levels in 20 of 24 persons.

Adolescent↗