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Parasite-specific immunomodulatory functions of filarial cystatin
Peter Schierack1, Richard Lucius, Bettina Sonnenburg
1Department of Molecular Parasitology, Humboldt University, Berlin, Germany.
Abstract:
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.
Insights
Filarial nematode cystatins suppress host immune cells more effectively than those from free-living worms. This difference in immune modulation may reflect parasitic adaptations of filarial cystatins.
Area of Science:
- Immunology
- Parasitology
- Molecular Biology
Background:
- Cystatins from parasitic nematodes are known pathogenicity factors.
- They downregulate host T-cell proliferation and induce anti-inflammatory responses.
Purpose of the Study:
- To compare the immunomodulatory effects of filarial nematode cystatins with homologous proteins from the free-living nematode Caenorhabditis elegans.
- To investigate the functional differences in protease inhibition and cytokine induction.
Main Methods:
- Biochemical characterization of cystatin protease inhibition activity against human cathepsins B, L, and S.
- Assays for T-cell proliferation using human peripheral blood mononuclear cells (PBMC) and murine spleen cells.
- Measurement of cytokine production (IL-10, IL-12, IFN-gamma) and nitric oxide induction in immune cells.
Main Results:
- Both filarial and C. elegans cystatins inhibited human cathepsins, with C. elegans cystatins showing stronger inhibition of cathepsin B.
- Filarial cystatins significantly suppressed PBMC and spleen cell proliferation, while C. elegans cystatins had a much weaker effect.
- Filarial cystatins increased IL-10 production, whereas C. elegans cystatins induced IL-12 and IFN-gamma.
Conclusions:
- Filarial cystatins exhibit distinct immunomodulatory properties compared to C. elegans cystatins, notably a stronger suppression of host cell proliferation and induction of anti-inflammatory cytokines.
- These differences suggest that specific structural or functional characteristics of filarial cystatins are adaptations for parasitic survival.
- The study highlights the specialized roles of nematode cystatins in host-parasite interactions.