IL-12 and TNF-α production by dendritic cells stimulated with Schistosoma mansoni schistosomula tegument is TLR4- and MyD88-dependent

Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, A. Belo Horizonte, Minas Gerais, Brazil.
Immunology letters (Impact Factor: 2.51). 07/2009; 125(1):72-7. DOI: 10.1016/j.imlet.2009.06.004
Source: PubMed


Schistosoma mansoni schistosomula are the most susceptible parasite life stage to host immune system attack. Complex host-parasite interactions take place on Schistosoma tegument, which is a unique double membrane structure involved in nutrition and immune evasion. Herein, we have demonstrated that schistosomula tegument (Smteg) activates Dendritic cells to produce IL-12p40, TNF-alpha and also to up-regulate the co-stimulatory molecules CD40 and CD86. Moreover, using DCs derived from MyD88-, TLR2-, TLR4- and TLR9-deficient mice we have shown that the ability of Smteg to activate DCs to produce IL-12 and TNF-alpha involves TLR4/Smteg interaction and MyD88 signaling pathway. Finally, our findings lead us to conclude that TLR4 is a key receptor involved in Smteg induction of pro-inflammatory cytokines.

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    • "Furthermore , the studies that used gene silencing through RNAi technique could clarify the importance of some proteins, such as cathepsins [41] [42] and tetraspanins [43] for parasite development and survival. The same membrane protein was identified in adult worm tegument preparations using Mass spectrometry (MS-)-based proteomics [33] [34] together with genome, transcriptome and genetic maps information [3, 44–46]. Recently a proteomic analysis demonstrated that Sm29 and Sm200 are linked to parasite surface membrane through a GPI-anchor [47] while the most abundant protein in adult worm tegument, among the investigated molecules, are aquaporin, dysferlin, TSP-2, and ATP diphosphohydrolase [48]. "
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    ABSTRACT: The development of a vaccine against schistosomiasis and also the availability of a more sensitive diagnosis test are important tools to help chemotherapy in controlling disease transmission. Bioinformatics tools, together with the access to parasite genome, published recently, should help generate new knowledge on parasite biology and search for new vaccines or therapeutic targets and antigens to be used in the disease diagnosis. Parasite surface proteins, especially those expressed in schistosomula tegument, represent interesting targets to be used in vaccine formulations and in the diagnosis of early infections, since the tegument represents the interface between host and parasite and its molecules are responsible for essential functions to parasite survival. In this paper we will present the advances in the development of vaccines and diagnosis tests achieved with the use of the information from schistosome genome focused on parasite tegument as a source for antigens.
    Journal of Parasitology Research 10/2012; 2012(3):541268. DOI:10.1155/2012/541268
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    • "Recently we have demonstrated that Smteg is able to activate bone marrow dendritic cells (BMDC) by up-regulating the expression of essential co-stimulatory molecules, such as CD40 and CD86, and also by inducing the production of IL-12p40 and TNFa cytokines in a TLR-4 dependent manner (Durães et al., 2009). "
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    ABSTRACT: The Schistosoma mansoni tegument interaction with the immune system plays a key role in disease establishment or elimination. We have recently demonstrated that S. mansoni schistosomula tegument (Smteg) is able to activate innate immune response and to induce protective immunity in a vaccine formulation with Freunds adjuvant. In this work, we evaluated the ability of Smteg to elicit protection in the absence of adjuvant. Smteg mice immunization resulted in significant antibody production, increased percentage of CD4+IFN-g+ and CD4+IL-10+ cells in spleen and increased production of IFN-g and IL-10 by spleen cells, but failed to reduce parasite burden, female fecundity and morbidity. We also demonstrated that BMDC stimulation with Smteg resulted in significant IL-10 production. Our results demonstrate that Smteg has immune modulatory proprieties.
    Acta tropica 07/2012; 124(2):140-6. DOI:10.1016/j.actatropica.2012.07.007 · 2.27 Impact Factor
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    • "It has been recently demonstrated that the larvae schistosomula tegument activated dendritic cells (DC) to produce IL-12p40, TNF-α and also co-stimulatory molecules CD40 and CD86 through a TLR4-dependent pathway [57]. This finding is especially important because it has been shown that mHMGB1 acts as adjuvant via DC activation, maturation and mobilization [42]. "
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    ABSTRACT: The helminth Schistosoma mansoni parasite resides in mesenteric veins where fecundated female worms lay hundred of eggs daily. Some of the egg antigens are trapped in the liver and induce a vigorous granulomatous response. High Mobility Group Box 1 (HMGB1), a nuclear factor, can also be secreted and act as a cytokine. Schistosome HMGB1 (SmHMGB1) is secreted by the eggs and stimulate the production of key cytokines involved in the pathology of schistosomiasis. Thus, understanding the mechanism of SmHMGB1 release becomes mandatory. Here, we addressed the question of how the nuclear SmHMGB1 can reach the extracellular space. We showed in vitro and in vivo that CK2 phosphorylation was involved in the nucleocytoplasmic shuttling of SmHMGB1. By site-directed mutagenesis we mapped the two serine residues of SmHMGB1 that were phosphorylated by CK2. By DNA bending and supercoiling assays we showed that CK2 phosphorylation of SmHMGB1 had no effect in the DNA binding activities of the protein. We showed by electron microscopy, as well as by cell transfection and fluorescence microscopy that SmHMGB1 was present in the nucleus and cytoplasm of adult schistosomes and mammalian cells. In addition, we showed that treatments of the cells with either a phosphatase or a CK2 inhibitor were able to enhance or block, respectively, the cellular traffic of SmHMGB1. Importantly, we showed by confocal microscopy and biochemically that SmHMGB1 is significantly secreted by S. mansoni eggs of infected animals and that SmHMGB1 that were localized in the periovular schistosomotic granuloma were phosphorylated. We showed that secretion of SmHMGB1 is regulated by phosphorylation. Moreover, our results suggest that egg-secreted SmHMGB1 may represent a new egg antigen. Therefore, the identification of drugs that specifically target phosphorylation of SmHMGB1 might block its secretion and interfere with the pathogenesis of schistosomiasis.
    PLoS ONE 08/2011; 6(8):e23572. DOI:10.1371/journal.pone.0023572 · 3.23 Impact Factor
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