Modulation of the host immune system by phosphorylcholine-containing glycoproteins secreted by parasitic filarial nematodes.
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Phosphorylcholine (PC) is increasingly becoming recognised as a carbohydrate-associated component of a wide variety of procaryotic and eucaryotic pathogens. Studies employing nematode PC-containing molecules indicate that it possesses a plethora of immunomodulatory activities. ES-62 is a PC-containing glycoprotein, which is secreted by the rodent filarial nematode Acanthocheilonema viteae and which provides a model system for the dissection of the mechanisms of immune evasion induced by related PC-containing glycoproteins expressed by human filarial nematodes. At concentrations equivalent to those found for PC-containing molecules in the bloodstream of parasitised humans, ES-62 is able to inhibit antigen receptor-stimulated proliferation of B and T lymphocytes in vitro and in vivo. The active component of ES-62 appears to be PC, as PC conjugated to albumin or even PC alone broadly mimic the results obtained with ES-62. PC-induced impaired lymphocyte responsiveness appears to reflect uncoupling of the antigen receptors from key intracellular proliferative signalling events such as the phosphoinositide 3-kinase, protein kinase C and Ras mitogen-activating protein kinase pathways. Although PC-ES-62 can desensitise B and T cells, not all cells are affected, and in fact it is still possible to generate an antibody response to the molecule. Dissection of this response indicates that it is of the TH-2 type. This appears to reflect the ability of ES-62 to direct the polarity of the T cell response by suppressing the production of proinflammatory cytokines, inducing the induction of anti-inflammatory cytokines and by driving the maturation of dendritic cells that direct TH-2 T cell responses. (+info)
B-cell deficiency suppresses vaccine-induced protection against murine filariasis but does not increase the recovery rate for primary infection.
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To establish the role of B cells and antibodies in destroying filariae, mice lacking mature B cells and therefore unable to produce antibodies were used. Litomosoides sigmodontis offers a good opportunity for this study because it is the only filarial species that completes its life cycle in mice. Its development was compared in B-cell-deficient mice (BALB/c muMT mice) and wild-type BALB/c mice in two different in vivo situations, vaccination with irradiated larvae and primary infection. In all cases, mice were challenged with subcutaneous inoculation of 40 infective larvae. Vaccine-induced protection was suppressed in B-cell-deficient mice. In these mice, eosinophils infiltrated the subcutaneous tissue normally during immunization; however, their morphological state did not change following challenge inoculation, whereas in wild-type mice the percentage of degranulated eosinophils was markedly increased. From this, it may be deduced that the eosinophil-antibody-B-cell complex is the effector mechanism of protection in vaccinated mice and that its action is fast and takes place in the subcutaneous tissue. In primary infection, the filarial survival and growth was not modified by the absence of B cells. However, no female worm had uterine microfilariae, nor did any mice develop a patent infection. In these mice, concentrations of type 1 (gamma interferon) and type 2 (interleukin-4 [IL-4], IL-5 and IL-10) cytokines in serum were lower and pleural neutrophils were more numerous. The effects of the muMT mutation therefore differ from those in B1-cell-deficient mice described on the same BALB/c background, which reveal a higher filarial recovery rate and microfilaremia. This outlines B2-cell-dependent mechanisms as favorable to the late maturation of L. sigmodontis. (+info)
Expansion of NK cells with reduction of their inhibitory Ly-49A, Ly-49C, and Ly-49G2 receptor-expressing subsets in a murine helminth infection: contribution to parasite control.
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Natural killer cell-associated direct cytotoxicity and cytokine production are crucial mechanisms for early innate host resistance against viruses, bacteria, or protozoa. The engagement of inhibitory NK cell receptors can influence host responses to viruses. However, these receptors have not been investigated to date in parasitic infections, and little is known about the role of NK cells in the defense against helminths. Therefore, we have correlated the frequencies of cells expressing the pan-NK marker DX5 and subsets bearing inhibitory Ly-49 receptors with worm survival and cytokine production during infection with Litomosoides sigmodontis in BALB/c mice (H2(d)), the only fully permissive model of filariasis. A marked influx of DX5(+)/CD3(-) NK cells and DX5(+)/CD3(+) T cells into the pleural cavity, where the parasites were located, was observed. The frequency of pleural NK cells expressing the H2(d)-reactive inhibitory receptors Ly-49A, Ly-49C, or Ly-49G2 declined most strongly compared with spleen and blood. In the peripheral blood, longitudinal analysis revealed an early and stable reduction of Ly-49C(+) and Ly-49G2(+) NK cells, a subsequent significant increase of the entire NK cell and DX5(+)/CD3(+) T cell populations, and a reduction in the Ly-49A(+) subset. The in vivo depletion of NK cells strongly enhanced the worm load and influenced IL-4 and IL-5 plasma levels. These data demonstrate a new role for NK cells in the host defense against filariae and, for the first time, alterations of Ly-49 receptor-expressing NK cell subsets in a parasitic infection. (+info)
Pelecitus helicinus Railliet & Henry, 1910 (Filarioidea, Dirofilariinae) and other nematode parasites of Brazilian birds.
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We report Pelecitus helicinus Railliet & Henry, 1910 from 13 species of birds of 2 orders and 7 families, collected from the states of Sao Paulo and Mato Grosso, Brazil. All 13 constitute new host records for this nematode. In addition, we report the first record of Aprocta golvani Diaz-Ungria, 1963 from Brazil and Monasa nigrifrons (Bucconidae), as well as a number of other nematode records from Neotropical birds. (+info)
Cloning and expression analysis of two mucin-like genes encoding microfilarial sheath surface proteins of the parasitic nematodes Brugia and Litomosoides.
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In several filarial genera the first stage larvae (microfilariae) are enclosed by an eggshell-derived sheath that provides a major interface between the parasite and the host immune system. Analysis of the polypeptide constituents of the microfilarial sheath from the cotton rat filaria Litomosoides sigmodontis identified two abundant surface glycoproteins: Shp3a and Shp3. The corresponding genes and the orthologues of the human parasite Brugia malayi and the rodent filaria Brugia pahangi were cloned and sequenced. They encode secreted, mucin-like proteins with N-terminal Ser/Thr-rich repeats and a C-terminal anchor domain rich in aromatic amino acids. About 75% of the protein molecular masses result from post-translational modifications. The Ser/Thr-rich motifs are supposed to serve as targets for dimethylaminoethanol-phosphate substitutions. These modifications were detected only on the sheaths of the late developmental stage of stretched microfilariae, corresponding with the expression of the proteins in the epithelium of the distal part of the uterus and the specific transcription of shp3 and shp3a in the anterior female worm segment. Genomic analysis of all three species demonstrated a conserved linkage of the two genes. Their transcripts undergo cis- and trans-splicing. The transcription start sites of the primary transcripts were determined for the L. sigmodontis genes. The core promoter regions are remarkably conserved between the paralogue genes Ls-shp3a and Ls-shp3 and their orthologues in Brugia, implicating conserved regulatory elements. (+info)
Parasite-specific immunomodulatory functions of filarial cystatin.
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Cystatins of parasitic nematodes are well-described pathogenicity factors which contribute to downregulation of T-cell proliferation of their hosts and induce anti-inflammatory cytokine responses. We compared the immunomodulatory effects of two cystatins of the filarial nematodes Onchocerca volvulus and Acanthocheilonema viteae with two homologous proteins of the free-living nematode Caenorhabditis elegans. Like filarial cystatins, the C. elegans cystatins (rCysele1 and rCysele2) possessed domains relevant for inhibition of papain-like proteases and were biologically active inhibitors of human cathepsins B, L, and S. However, the inhibition of cathepsin B by C. elegans cystatin was much stronger. C. elegans cystatins lacked a domain involved in inhibition of legumain-like proteases that was present in O. volvulus cystatin. Filarial cystatins suppressed the proliferation of human peripheral blood mononuclear cells (PBMC) and murine spleen cells, while the C. elegans cystatins had this effect to a much lesser extent. Whereas filarial cystatins markedly increased the production of interleukin (IL)-10, C. elegans cystatins increased the production of IL-12 and gamma interferon (IFN-gamma) by human PBMC. The cystatins of both the filariae and C. elegans induced an upregulation of inducible nitric oxide by IFN-gamma-stimulated murine macrophages. These data suggest that filarial cystatins but not the C. elegans cystatins downregulate proliferative responses of host cells due to characteristics which might reflect an adaptation of filariae to their parasitic life style. (+info)
Antibiotic therapy in murine filariasis (Litomosoides sigmodontis): comparative effects of doxycycline and rifampicin on Wolbachia and filarial viability.
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The symbiosis of filarial nematodes and rickettsial Wolbachia endobacteria has been exploited as a target for antibiotic therapy of filariasis. Depletion of Wolbachia after tetracycline treatment results in filarial sterility because of interruption of embryogenesis and inhibits larval development and adult worm viability. The aim of this study was to investigate if antibiotic intervention of BALB/c mice infected with the rodent filaria Litomosoides sigmodontis with rifampicin or the combination of rifampicin and doxycycline can be used to shorten the treatment period. Both regimens, when given over a period of 14 days initiated with infection, were sufficient to deplete Wolbachia as evidenced by immunohistology and semiquantitative PCR. Worm development and filarial load were significantly reduced in experiments followed up until 63 days p.i. The therapy inhibited embryogenesis and led to filarial sterility. In contrast, treatment with doxycycline alone for 21 days led only to a modest reduction of Wolbachia, filarial growth retardation, worm viability and fertility. In conclusion, the combination of antirickettsial drugs could be used as a suitable tool to explore the minimum duration of therapy required for the depletion of Wolbachia in parasitized hosts subsequent to the onset of patency in human and animal filariasis and the prevention of adverse reactions in human infections. (+info)
Arthropod and filarioid parasites associated with wild rodents in the northeast marshes of Buenos Aires, Argentina.
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During 1995, 16 species of arthropods and 2 species of filarioids, totaling 1 287 specimens were collected from 64 wild rodents captured in the Hudson Natural Reserve, Buenos Aires, Argentina. Infestation parameters and indexes were analyzed. Host specific richness was S = 6, diversity H = 1.48, and relative density RDI = 40%. High values of parasite species richness and diversity were found on Oligoryzomys delticola (S = 9; H = 1.40), Oxymycterus rufus (S = 9; H = 1.37), and Oligoryzomys flavescens (S = 9; H = 1.28), followed by Scapteromys aquaticus (S = 6; H = 0.17), and Akodon azarae (S = 4; H = 1.20). Deltamys kempi was infested only by Androlaelaps rotundus. O. delticola and O. flavescens showed the highest similarity index (O = 74.19%), followed by O. flavescens with S. aquaticus, as a result of historical processes and shared microhabitats. Considering arthropods-filarioids associations, significant affinity was observed in Litomosoides bonaerensis with Hoplopleura travassosi, Laelaps paulistanensis, and Gigantolaelaps wolffsohni. (+info)