Efficacy of five annual single doses of diethylcarbamazine for treatment of lymphatic filariasis in Fiji. (1/222)

Annual single-dose treatments with diethylcarbamazine citrate (DEC) at a dose of 6 mg/kg have been reported effective in reducing microfilariae (mf) rate and density and applicable to large-scale filariasis control campaigns. However, the efficacy of such treatments has not been studied quantitatively in relation to different pretreatment levels of endemicity. This study of 32 villages in Fiji revealed that five treatments repeated annually steadily reduced village mf rate, and that the degree of reduction was not influenced by pretreatment levels of mf density or rate. This indicates that an annual dosage scheme is applicable to high-endemicity areas. The results also suggest that such treatment affected juvenile forms of Wuchereria bancrofti and may prevent them from reproducing.  (+info)

Anti-filarial IgG4 in men and women living in Brugia malayi-endemic areas. (2/222)

To assess whether antifilarial IgG4 can be used to study various epidemiological facets of filarial infections, we studied this isotype in 238 individuals resident in areas endemic for brugian filariasis, focusing on the differences between men and women. In the study area, the prevalence of microfilariae was 6.7% and the prevalence of antifilarial IgG4 was 49.2%. All microfilariae carriers were positive for antifilarial IgG4, whereas a proportion of the endemic normals (94/208) and clephantiasis patients (7/14) had IgG4 antibodies to filarial antigens. Data were analysed as a function of gender in distinct clinical groups and stratified for age. The prevalence of microfilariae was higher in males in all age groups, as reflected in significantly higher antifilarial IgG4 antibody levels compared to females. The prevalence of IgG4 increased to reach a plateau at the age of 30 years in both males and females. These results indicate that antifilarial IgG4 antibodies can reflect the differences in the extent of infection in males and females as measured by microfilarial counts, and that this parameter can be used for epidemiological assessments of filarial infection.  (+info)

Immunity in experimental murine filariasis: roles of T and B cells revisited. (3/222)

We have reevaluated the contributions of T and B cells in Brugia malayi infection by utilizing knockout mice on a uniform background (C57BL/6J). We find that B-cell-deficient mice are more permissive to infection than T-cell-deficient mice.  (+info)

Homologs of the Caenorhabditis elegans masculinizing gene her-1 in C. briggsae and the filarial parasite Brugia malayi. (4/222)

The masculinizing gene her-1 in Caenorhabditis elegans (Ce-her-1) encodes a novel protein, HER-1A, which is required for male development. To identify conserved elements in her-1 we have cloned and characterized two homologous nematode genes: one by synteny from the closely related free-living species C. briggsae (Cb-her-1) and the other, starting with a fortuitously identified expressed sequence tag, from the distantly related parasite Brugia malayi (Bm-her-1). The overall sequence identities of the predicted gene products with Ce-HER-1A are only 57% for Cb-HER-1, which is considerably lower than has been found for most homologous briggsae genes, and 35% for Bm-HER-1. However, conserved residues are found throughout both proteins, and like Ce-HER-1A, both have putative N-terminal signal sequences. Ce-her-1 produces a larger masculinizing transcript (her-1a) and a smaller transcript of unknown function (her-1b); both are present essentially only in males. By contrast, Cb-her-1 appears to produce only one transcript, corresponding to her-1a; it is enriched in males but present also in hermaphrodites. Injection of dsRNA transcribed from Cb-her-1 into C. briggsae hermaphrodites (RNA interference) caused XO animals to develop into partially fertile hermaphrodites. Introducing a Cb-her-1 construct as a transgene under control of the C. elegans unc-54 myosin heavy chain promoter caused strong masculinization of both C. briggsae and C. elegans hermaphrodites. Introduction of a similar Bm-her-1 construct into C. elegans caused only very weak, if any, masculinization. We conclude that in spite of considerable divergence the Cb gene is likely to be a functional ortholog of Ce-her-1, while the function of the distantly related Bm gene remains uncertain.  (+info)

A novel serpin expressed by blood-borne microfilariae of the parasitic nematode Brugia malayi inhibits human neutrophil serine proteinases. (5/222)

Serine proteinase inhibitors (serpins) play a vital regulatory role in a wide range of biological processes, and serpins from viruses have been implicated in pathogen evasion of the host defence system. For the first time, we report a functional serpin gene from nematodes that may function in this manner. This gene, named Bm-spn-2, has been isolated from the filarial nematode Brugia malayi, a causative agent of human lymphatic filariasis. Polymerase chain reaction (PCR) and Western blot experiments indicate that Bm-spn-2 is expressed only by microfilariae (Mf), which are the long-lived blood-dwelling larval stage. A survey of the greater than 14,000 expressed sequence tags (ESTs) from B malayi deposited in dbEST shows that greater than 2% of the ESTs sequenced from Mf cDNA libraries correspond to Bm-spn-2. Despite its abundance in the microfilarial stage, Bm-spn-2 has not been found in any other point in the life cycle. The predicted protein encoded by Bm-spn-2 contains 428 amino acids with a putative signal peptide. Antibodies to recombinant Bm-SPN-2 protein react specifically with a 47.5-kD native protein in Mf extract. Bm-SPN-2 is one of the largest of the 93 known serpins, due to a 22 amino acid carboxy-terminal extension, and contains the conserved serpin signature sequence. Outside these regions, levels of homology are low, and only a distant relationship can been seen to a Caenorhabditis elegans serpin. The Bm-spn-2 gene contains 6 introns, 2 of which appear to be shared by both nematode species. The B malayi introns have an extended and conserved 3' splice site and are relatively large compared with C elegans. A panel of mammalian serine proteinases were screened and Bm-SPN-2 protein was found to specifically inhibit enzymatic activity of human neutrophil cathepsin G and human neutrophil elastase, but not a range of other serine proteinases. It is possible that Bm-SPN-2 could function as a stage-specific serpin in the blood environment of the microfilarial parasite in protection from human immunity and thus may be a good candidate for protective vaccine.  (+info)

Comparative analysis of glycosylated and nonglycosylated filarial homologues of the 20-kilodalton retinol binding protein from Onchocerca volvulus (Ov20). (6/222)

Ov20 is a structurally novel 20-kDa retinol binding protein secreted by Onchocerca volvulus. Immunological and biological investigation of this protein has been hampered by the inability to maintain O. volvulus in a laboratory setting. In an effort to find a system more amenable to laboratory investigation, we have cloned, sequenced, and expressed cDNA encoding homologues of Ov20 from two closely related filarial species, Brugia malayi (Bm20) and Acanthocheilonema viteae (Av20). Sequence comparisons have highlighted differences in glycosylation of the homologues. We present here an analysis of mouse immune responses to Ov20, Bm20, and Av20. The results suggest a strong genetic restriction in response to native Bm20 that is overcome when recombinant, nonnative material is used. Reactivity of human filarial sera to the three recombinant proteins confirmed previous specificity studies with Ov20 but highlighted important differences in the reactivity patterns of the O. volvulus and B. malayi homologues that may be due to differences in glycosylation patterns. Ov20 is a dominant antigen in infected individuals, while Bm20 is not. The availability of the B. malayi homologue enabled us to use defined murine reagents and inbred strains for genetic analysis of responsiveness in a way that is not possible for Ov20. However, the close sequence similarity between Ov20 and Av20 suggests that the A. viteae model may be more suited to the investigation of the biological functions of Ov20.  (+info)

Calgranulin C has filariacidal and filariastatic activity. (7/222)

The calgranulins are a family of calcium- and zinc-binding proteins produced by neutrophils, monocytes, and other cells. Calgranulins are released during inflammatory responses and have antimicrobial activity. Recently, one of the calgranulins, human calgranulin C (CaGC), has been implicated as an important component of the host responses that limit the parasite burden during filarial nematode infections. The goal of this work was to test the hypothesis that human CaGC has biologic activity against filarial parasites. Brugia malayi microfilariae and adults were exposed in vitro to 0.75 to 100 nM recombinant human CaGC. Recombinant CaGC affected adult and larval parasites in a dose-dependent fashion. Microfilariae were more sensitive to the action of CaGC than were adult parasites. At high levels, CaGC was both macrofilariacidal and microfilariacidal. At lower levels, the percentage of parasites killed was dependent on the level of CaGC in the culture system. The larvae not killed had limited motility. The filariastatic effect of low-level CaGC was reversed when the CaGC was removed from the culture system. Immunohistochemical analysis demonstrated that human CaGC accumulated in the cells of the hypodermis-lateral chord of adult and larval parasites. The antifilarial activity of CaGC was not due to the sequestration of zinc. Thus, the cellular and molecular mechanisms that result in the production and release of CaGC in humans may play a key role in the regulation of filarial parasite numbers.  (+info)

B1 B lymphocytes play a critical role in host protection against lymphatic filarial parasites. (8/222)

Host defense against multicellular, extracellular pathogens such as nematode parasites is believed to be mediated largely, if not exclusively, by T lymphocytes. During our investigations into the course of Brugia malayi and Brugia pahangi infections in immunodeficient mouse models, we found that mice lacking B lymphocytes were permissive for Brugian infections, whereas immunocompetent mice were uniformly resistant. Mice bearing the Btk(xid) mutation were as permissive as those lacking all B cells, suggesting that the B1 subset may be responsible for host protection. Reconstitution of immunodeficient recombination activating gene (Rag)-1(-/)- mice with B1 B cells conferred resistance, even in the absence of conventional B2 lymphocytes and most T cells. These results suggest that B1 B cells are necessary to mediate host resistance to Brugian infection. Our data are consistent with a model wherein early resistance to B. malayi is mediated by humoral immune response, with a significant attrition of the incoming infectious larval load. Sterile clearance of the remaining parasite burden appears to require cell-mediated immunity. These data raise the possibility that the identification of molecule(s) recognized by humoral immune mechanisms might help generate prophylactic vaccines.  (+info)

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