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Parasitic nematodes do not multiply in definitive hosts, but they do molt, grow and mature for a certain period after infection, after which they devote their energies almost entirely to egg production. In this review, Sara Lustigman describes key metabolic enzymes that are essential to the development of the larval stages of Onchocerca volvulus in the host, making them potential therapeutic targets.
Nematode spermatozoa, unlike their mammalian counterparts, are nonflagellated crawling cells. The pseudopod of these cells contains the major sperm protein (MSP) which comprises more than 15% of the protein in the sperm. MSP is presumed to function as a cytoskeletal element involved in motility. An Ascaris MSP cDNA sequence was used as a probe to identify and isolate Onchocerca volvulus MSP clones from a lambda gt11 genomic library. Two clones, OVGS-1 (765 bp) and OVGS-2 (1765 bp), were characterized by restriction endonuclease mapping and sequence analysis. Both genomic clones contain MSP protein coding regions of 99 and 282 bp separated by an intervening sequence of 153 bp. The genes OVGS-1 and OVGS-2 are 95% similar in nucleotide sequence in the protein coding regions, but only 79% similar in their intron sequences. A number of potential regulatory sequences in the flanking regions and at the exon/intron junctions of the O. volvulus MSP genes are in good agreement with consensus sequences in other eukaryotic cells. The nucleotide sequence of the O. volvulus MSP genes were over 80% similar to the Ascaris MSP cDNA sequence and 79% similar to the Caenorhabditis MSP-3 cDNA. The predicted amino acid sequence of the O. volvulus MSPs were 96% similar to each other, 90-91% similar to Ascaris MSP and 81-82% similar to Caenorhabditis MSP-3. These results offer evidence that the MSP sequences have been highly conserved throughout nematode evolution but are variable in their genomic organization and the presence of introns.
Crude aqueous Litomosoides carinii adult worm extract was used as antigen for the detection of antibodies in sera from African patients with proven onchocerciasis (n = 45) resident in rural endemic areas of Togo and Sierra Leone. In 71% of cases this extract was found to produce 1 to 5 precipitation arcs in immunoelectrophoresis. Using a crude aqueous extract from adult Onchocerca volvulus, precipitation tests were positive in 75% of cases. The complexity of the L. carinii crude extract was shown by PAG-disc electrophoresis, PAG-electrofocusing, immunoelectrophoresis and crossed immunoelectrophoresis with the appropriate rabbit-antiserum. An antigen detecting onchocercal antibodies was isolated by two step preparative flat bed electrofocusing in granulated gel (PEGG). The antigen (pI 6.55, molecular weight 55 to 60 kd as estimated by SDS-PAG electrophoresis) was very suitable for antibody demonstration in double diffusion test and immunoelectrophoresis. Preliminary controls for specificity were performed by diffusing the antigen against sera from human and animal helminthoses including filarial infections. In contrast to the crude L. carinii extract no reaction was observed with sera from helminthic infections others than filariasis.
A novel type of N-acetyltransferase, clearly different from the nuclear and cytosolic polyamine N-acetyltransferases of mammals, was recently found in the intestinal nematode Ascaris suum. The occurrence of this putrescine N-acetylating enzyme has also been noted in the filarial parasite Onchocerca volvulus. The enzyme was partially purified from adults of O. volvulus and A. suum by chromatography on DEAE-cellulose and cadaverine-Sepharose. Substrate specificities of the filarial enzyme resemble those of the N-acetyltransferase from A. suum, with respect to its preference for putrescine and other diamines above polyamines and histones. Additionally, both nematode enzymes acetylated histamine, whereas dopamine and serotonin were not accepted as substrates. The activities of the N-acetyltransferase from O. volvulus and A. suum were potently inhibited by the drug berenil; the type of inhibition was competitive with respect to putrescine. The inhibition constants for berenil were determined as 4.2 and 1.2 microM for the enzymes of O. volvulus and A. suum, the Km values for putrescine were found to be 330 microM and 250 microM, respectively. Putrescine N-acetyltransferase is discussed as a regulatory step in the degradation of excessive polyamines via polyamine oxidase to putrescine. At this branching point, putrescine is retained in the cell for de novo synthesis of spermidine and spermine, catabolized via diamine oxidase or acetylated to a suitable transport product for excretion.
The pathogenesis of tissue damage in filarial infections involves the generation of inflammatory mediators by interaction of parasite surfaces with the host immune response. In the presence of a heavy parasite burden, the tremendous potential for development of adverse local or systemic inflammatory responses may be appreciated by knowledge of the cumulative surface area represented by circulating microfilariae. The approximate surface area of a single microfilariae of Onchocerca volvulus was calculated using mathematical formulae for standard geometrical shapes and values derived from serial measurements of electron micrographs. Numerical values for the surface area represented by large numbers of microfilariae are given and compared to surface areas of the host which can harbor many millions of microfilariae.
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.
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.
The nucleotide sequence of a cDNA copy of the Dirofilaria immitis paramyosin gene was determined. The sequence was 2545 nucleotides in length, consisting of a single open reading frame of 848 amino acids capable of encoding a protein with a calculated molecular weight of 98,000. The cDNA clone was not complete, but probably includes over 97% of the coding region of the gene. We have previously observed that the cloned D. immitis paramyosin is recognized by sera from humans infected with Onchocerca volvulus. To determine the extent of homology at the protein level, we screened a cDNA library of O. volvulus with an antiserum made against D. immitis paramyosin. Ten recombinant clones were partially sequenced, comprising a total of 1186 nucleotides or 389 amino acids. The amino acid sequence of D. immitis paramyosin was 99% identical to the O. volvulus paramyosin. We also compared the amino acid sequence to other cloned paramyosins, and noted that 92% of the amino acids were identical to those of Caenorhabditis elegans, and 34% identical to those of Schistosoma mansoni. Comparison of the paramyosin sequence between different species revealed a hierarchy of similarities: (1) a 7-amino-acid repeat with apolar residues in the a and d position as the most conserved, followed by (2) the amino acid sequence and (3) the DNA sequence.
The response of 45 severely infected onchocerciasis patients to relatively high doses of diethylcarbamazine citrate (DEC-C) has been determined. The treatment comprised two sequential phases; the first phase comprised the topical applications of a DEC-C lotion and of the anti-inflammatory steroid betamethasone. The second phase comprised the daily oral administration of high doses of DEC-C (30 mg/kg body wt) for seven days. Onchocerca volvulus microfilarial (o.v.mf.) counts in skin snips of the 45 patients decreased by 96 +/- 1.5% after 5 days of treatment with topical DEC-C lotion. Following the administration of oral DEC, the average O.v.mf. counts in the skin snips at days 51, 97, and 143 remained decreased by 85 to 93%. The mean O.v.mf. counts in 10 nodules excised from 5 treated patients at day 77 had decreased by 93% compared to the mean O.v.mf. counts in 11 nodules taken from 5 untreated patients with similar initial O.v.mf. infection. No visual loss resulted from the treatment.
Two sets of controlled experiments were conducted, using 13 adult onchocerciasis patients from a village in the hyperendemic rain-forest zone of Western Nigeria, to determine the effect of the excision of one or two onchocercal nodules on the concentration of microfilariae in the skin. The results show that, in patients with established infections who are exposed to continuing reinfection, nodulectomy per se does not reduce the microfilarial density, overall or in the same anatomical region from which the nodule is excised, to any significant degree. It is therefore concluded that the indirect assessment of the activity of test drugs against the adult Onchocerca volvulus by serial estimation of microfilarial concentrations over a period of about 24 months is unlikely to be compromised by limited selective nodulectomy.
Over the past 35 yr, diethylcarbamazine (DEC) has been the most widely used agent for the treatment of filarial diseases, particularly in onchocerciasis. The microfilaricidal action of DEC has been recently shown to be mediated by blood platelets with the additional triggering of a filarial excretory Ag (FEA). This FEA could be detected by using mAb in the serum of infected patients. By using one mAb (IA2(23] directed against Onchocerca volvulus and recognizing circulating Ag (Ab1), we purified by affinity chromatography the target molecule of IA2(23) (an O. volvulus glycoprotein recognized by IA2(23) mAb). This compound had a dose-dependent effect on the cytotoxic action of DEC-treated platelets. We subsequently produced an anti-idiotype mAb to Ab1 (Ab2), and considered the possibility of replacing the O. volvulus glycoprotein recognized by IA2(23) mAb by Ab2. Ab2 was selected according to its ability to inhibit the binding of radioiodinated Ab1 to the filarial target Ag. It induced the production of anti-O. volvulus antibodies (Ab3) in rats. At a constant concentration of DEC platelets, the addition of increasing amounts of Ab2 led to a dose-dependent cytotoxic effect against parasite larvae. Experiments performed with Ab2 on detergent solubilized surface proteins of platelets identified four bands of Mr 18, 26, 43.5, and 100 kDa, supporting the idea of the presence of binding sites on the platelets for a FEA required for the microfilaricidal cytotoxicity of DEC-treated platelets.
Populations of Simulium damnosum s.str. and S. sirbanum were examined for infections with filarial parasites during three years in the areas of Tcholliré and Touboro, at sites at different distances from Simulium breeding rivers, and in relation to villages with different endemicities of onchocerciasis. A total of 60,353 flies from 23 fly-catching sites were dissected. The overall infection rate was low, 11.8% of 35,357 parous flies dissected. 1681 flies (4.8% of the total parous) contained 3557 infective larvae, 68.8% of which were morphologically indistinguishable from Onchocerca volvulus and 31.2% were infective 'Type D' larvae of non-human origin, indicating a high degree of zoophily of the fly populations. It was estimated that only 20-40% of all bloodmeals were taken from man. The majority (54%) of all infective O. volvulus larvae were found in the heads of the flies, the remainder being in the thorax (34%) and abdomen (12%). Only 54% of the O. volvulus infective larvae left their vectors during a bloodmeal which, however, was not completed in most cases. During the rainy season infection rates with O. volvulus infective larvae were 3.5% of the total parous flies, as compared with 1.8% during the dry season. The average number of infective larvae of O. volvulus per infective fly was 2.6 and 2.2 during the rainy and dry seasons respectively. These variations in the vectorial efficiency of the fly populations, as well as variations from one site to another, could be explained by different survival rates and man-biting habits of the various vector populations during the dry and rainy seasons and in different regions, rather than by different endemic profiles of onchocerciasis in the human population. The intensity of transmission varied seasonally and was highest (1609 to 3076 infective larvae/man/year) near the main breeding sites, where transmission was almost perennial. At distances of more than 3 km from the river transmission was mainly restricted to the rainy season and the Annual Transmission Potential was below 200, whereas low to zero levels of transmission were measured inside villages more than 3 km distant from the river. The coefficient of variation of the Annual Transmission Potentials over the three years of studies was from 31% to 192% of the mean, being higher that the variations in the corresponding levels of the biting rates, due to the low numbers of infective flies dissected at sites with low transmission.(ABSTRACT TRUNCATED AT 400 WORDS)
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The majority of Onchocerca volvulus-infected persons show signs of cellular anergy, and long-time survival of adult and larval parasites in subcutaneous tissue is observed. The mechanisms leading to immunological hyporesponsiveness are poorly understood. Monocytes/macrophages represent a link between the innate and acquired immune system and are candidate cells to promote inflammatory and antiinflammatory processes. In the present study we have shown that products of microfilarial (O. volvulus) and adult (O. volvulus and O. ochengi) parasites affect monocytes in vitro. An early production of TNF-alpha by exposed monocytes was followed by the production of IL-10 and a reduced expression of HLA-DR and the costimulatory molecules B7-1 and B7-2, while other adhesion receptors remained unaffected. Downregulation of the functional membrane receptors failed to occur after treatment of the cells with anti-IL-10 antibodies. The engagement of CD14, a dominant membrane receptor on monocytes and major binding protein for lipopolysaccharides, was indicated by partial blocking of monocyte modulation by neutralizing antibodies to CD14 and by the antagonistic lipid A analog compound 406. Lipopolysaccharide-like molecules were detected in sterile products of O. volvulus stages which could originate from Wolbachia bacteria related to Gram-negative Rickettsiales, known to be abundant in the hypodermis and the female reproductive organs of O. volvulus. The present results indicate that the monocyte/macrophage may be a major target cell for immunomodulatory parasite-derived and intraparasitic, bacteria-derived molecules, thereby contributing to the host's cellular hyporesponsiveness.
A study was done to determine the importance of human migration from non-controlled endemic onchocerciasis foci to the river valleys that have been protected for the past 14 to 15 years by the vector control operations of the Onchocerciasis Control Programme in West Africa. The aim of the study was to assess the contribution of migrants to the prevalence and intensity of infection in villages from 5 major river valleys and their potential role in causing relapse of transmission once the vector is allowed to return. In Burkina Faso the migrant population varied from 0.0% to 18.1% of the village population, and averaged 4.9%. Migrants accounted only for 0.6% of the population in Ghanaian and Ivorian villages along the Black Volta river. The prevalence of infection was significantly higher in migrants (8.2%) than in non migrants (1.1%) in the surveyed villages in Burkina Faso, and 1.5% of migrants had infections with more than 16 microfilariae per snip as against 0.2% of non migrants. Nearly all infected migrants came from the south of the Côte d'Ivoire. The study shows that human migration has caused the importation of Onchocerca volvulus from non-controlled areas. However, the epidemiological importance of this phenomenon is limited because of the very small number of infected migrants per village while two-third of the infected migrants are believed to be infected with the less pathogenic forest strain of the parasite. Because migration patterns changes geographically and over time similar studies will be continued on a regular basis.