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Mammalian homologue of high mobility group box chromatin protein (HMGB) 1 was identified and cloned from human parasites, Schistosoma mansoni and S. haematobium. Sequence analyses showed that the parasite HMGB1s has 35-40% identity to human and rodent HMGB1s, and 33% identity to Caenorhabditis elegans HMGB1. Parasite HMGB1s also contains an A box and B box domain similar to mammalian HMGB1, however, it lacks the C-terminal tail that is present in mammalian HMGB1s. Analysis of the expression of HMGB1 in various life cycle stages of S. mansoni reveal S. mansoni HMGB1 (SmHMGB1) as a stage-specific protein, expressed abundantly in egg and adult female stages and at moderate levels in skin-stage schistosomula. Significant levels of SmHMGB1 were also present in excretory secretions of egg stages. Subsequent characterization studies showed that SmHMGB1 is a potent inducer of pro-inflammatory cytokines such as TNFalpha, IL-1Ralpha, IL-2Ralpha, IL-6, IL-13, IL-13Ralpha1, IL-15 and MIP-1alpha from mouse peritoneal macrophages. Pro-inflammatory activity, especially production of TNFalpha-inducing activity, appears to be a function of the B box domain protein. This was confirmed by both real-time reverse transcription PCR and by cytokine ELISA. Thus, results presented in this study suggest that SmHMGB1 may be a key molecule in the development of host inflammatory immune responses associated with schistosomiasis.
Mol Biochem Parasitol 2006 Feb
PMID:Cloning and characterization of a high mobility group box 1 (HMGB1) homologue protein from Schistosoma mansoni. 1624 38

Complete mitochondrial genome sequences for the schistosomes Schistosoma haematobium and Schistosoma. spindale have been characterized. S. haematobium is the causative agent of urinary schistosomiasis in humans and S. spindale uses ruminants as its definitive host; both are transmitted by freshwater snail intermediate hosts. Results confirm a major gene order rearrangement among schistosomes in all traditional Schistosoma species groups other than Schistosoma japonicum; i.e., species groups S. mansoni, S. haematobium, and S. indicum. These data lend support to the 'out of Asia' (East and Southeast Asia) hypothesis for Schistosoma. The gene order change involves translocation of atp6-nad2-trnA and a rearrangement of nad3-nad1 relative to other parasitic flatworm mt genomes so far sequenced. Gene order and tRNA secondary structure changes (loss and acquisition of the DHU and/or TPsiC arms of trnC, trnF, and trnR) between mitochondrial genomes of these and other (digenean and cestode) flatworms were inferred by character mapping onto a phylogeny estimated from nuclear small subunit rRNA gene sequences of these same species, in order to find additional rare genomic changes suitable as synapomorphies. Denser and wider taxon sampling of mt genomes across the Platyhelminthes will validate these putative characters.
Mol Phylogenet Evol 2006 May
PMID:The complete mitochondrial genomes of Schistosoma haematobium and Schistosoma spindale and the evolutionary history of mitochondrial genome changes among parasitic flatworms. 1646 18

Schistosomiasis, caused by parasitic helminths, remains a serious human disease in the tropics. Cercariae of Schistosoma mansoni infect their hosts by direct skin penetration, aided by secretions from acetabular and head glands. Both proteolytic and immunomodulatory properties have been ascribed to the released material, but to date only five isoforms of elastase and one putative anti-inflammatory protein (Sm16) have been cloned. We analyzed secretions from mechanically transformed cercariae by two-dimensional electrophoresis. An average gel image was created and compared with a separation of soluble larval extract, revealing a less complex spot pattern in the secretions with 60% of the spots matched to the larval extract. Subsequent tandem mass spectrometric analysis identified 48 spots from the released material, representing approximately 80% of its normalized volume. Twenty-nine of these are likely to originate in the vesicles, and 18 are likely to originate in the cytosol of the glands (the latter class being present due to holocrine secretion); one is unknown. The vesicular proteins were significantly more enriched than the cytosolic proteins in the released material when compared with the larval extract. A novel metalloproteinase (termed SmPepM8) was the second most abundant constituent after three isoforms of cercarial elastase. In addition, a dipeptidyl peptidase IV (SmDPP IV) was discovered but in much smaller quantity. A new serine protease inhibitor (SmSerp_c) was also prominent. Along with Sm16, four potential immunomodulators were identified, three with similarity to venom allergens (SmSCP_a, _b, and _c) and one with homology to the potassium channel blockers in scorpion venom (SmKK7). Interrogation of the expressed sequence tag database found transcripts encoding the majority of vesicular proteins present solely in the intramolluscan stages of the life cycle. Distinct patterns of radiolabel incorporation suggested three separate origins for the vesicular proteins. All the novel constituents merit investigation as vaccine candidates, and the potential immunomodulators merit investigation as therapeutic agents.
Mol Cell Proteomics 2006 May
PMID:Identification of novel proteases and immunomodulators in the secretions of schistosome cercariae that facilitate host entry. 1646 60

To date, glyceroneogenesis has only been described in mammals but we demonstrate in this paper that it could exist in the invertebrate Schistosoma mansoni, the parasitic helminth transmitted by fresh water molluscs and responsible for the major human endemic disease, schistosomiasis. Glyceroneogenesis is a phosphoenolpyruvate carboxykinase (PEPCK)-dependent process by which glycerol can be produced from precursors like glutamine and therefore represents a truncated gluconeogenic pathway. We have previously demonstrated the possible central role of glutamine in mollusc-schistosome interactions. In this work, we show that glutamine effectively promotes in vitro survival and protein synthesis in sporocysts, the intramolluscan larval stages of S. mansoni, possibly through its role as an energy source. However, the demonstration that PEPCK is massively expressed in these larval forms as compared to adult parasites, together with the observation that 3-mercaptopicolinate, a specific inhibitor of PEPCK, significantly reduces the effect of glutamine on sporocyst growth, suggest that glutamine could also be used for glucose or glycerol production. Results of [14C] glutamine incorporation confirmed that neosynthesis of glucose and mainly of glycerol occurred in sporocysts and was dependent on PEPCK activity. Therefore, our results strongly indicate that glyceroneogenesis could exist in schistosomes. Several hypotheses can be proposed concerning the importance of glycerol for the adaptation of this helminth to its host osmotic and energetic environment.
Mol Biochem Parasitol 2006 Jun
PMID:Glyceroneogenesis: an unexpected metabolic pathway for glutamine in Schistosoma mansoni sporocysts. 1652 33

Schistosomiasis is a chronic and debilitating disease caused by blood flukes (digenetic trematodes) of the genus Schistosoma. Schistosomiasis japonica, a zoonosis caused by Schistosoma japonicum, is endemic to the Philippines and China. We utilised a 22,575 feature custom oligonucleotide DNA microarray designed from public domain databases of schistosome-expressed sequence tags to explore differential gene expression between the Philippine (SJP) and Chinese (SJC) strains of S. japonicum, and between male and female S. japonicum. We found that 593, 664 and 426 probes were differentially expressed between the two geographical strains when we compared mix sexed adults, male worms and female worms. Additionally, the study revealed that 1163 male- and 1016 female-associated probes were differentially expressed in SJP whereas 1047 male- and 897 female-associated probes were differentially expressed in SJC. The study greatly expands previously published data of strain and gender-associated differential expression in S. japonicum. Further, these new data provide a stepping stone for understanding the complexities of the biology, sexual differentiation, maturation, and development of human schistosomes, signaling new approaches for identifying novel intervention and diagnostic targets against schistosomiasis.
Mol Cell Probes 2006 Oct
PMID:Oligonucleotide microarray analysis of strain- and gender-associated gene expression in the human blood fluke, Schistosoma japonicum. 1664 36

Many infectious diseases of global impact are caused by parasites. This includes diseases with protozoan etiology, such as malaria, African sleeping sickness, Chagas disease, toxoplasmosis, and amoebiasis, as well as diseases caused by metazoa, such as river blindness, schistosomiasis, ecchinococcosis, and ascariasis. Combined, parasitic diseases affect more than half the world's human population and are responsible for decreased gross national products and billions of dollars in lost earnings. Although the magnitude of the problem precludes quick solutions, there is reasonable hope that a better understanding of these organisms, especially the host-parasite interactions that underpin virulence and pathogenicity mechanisms, will provide new opportunities for rational intervention strategies. Yeast artificial chromosomes (YAC) have substantially aided in this endeavor by providing an unlimited access to defined parts of a parasite's genome, which, in turn, has facilitated a broad range of molecular studies. For example, YACs have facilitated positional cloning strategies to identify genes involved in antigenic variation and drug resistance mechanisms. Moreover, YACs have been invaluable tools for the many genome sequencing projects examining parasites. In this chapter, we provide a detailed protocol of how to generate representative YAC libraries from parasite genomes. This protocol can be applied to both protozoa and metazoa, and can even be used for YAC library construction of parasite material isolated from a single infected host.
Methods Mol Biol 2006
PMID:Construction of yeast artificial chromosome libraries from pathogens and nonmodel organisms. 1707 69

Available evidence suggests that, in African populations, systemic blood-dwelling parasitoses of mothers are associated with enhanced susceptibility to infection of their offspring. Thus, children born to mothers with filariasis or schistosomiasis are infected earlier, and offspring of mothers with placental Plasmodium falciparum at delivery, commonly referred to as pregnancy-associated malaria or PAM, are themselves at higher risk of developing parasitaemia during infancy. Since foetal/neonatal antigen-presenting cells (APC) are either immature or provide insufficient costimulatory signals to T cells, thus favouring tolerance induction, it is commonly assumed that soluble parasite components [protein antigens], transferred transplacentally and inducing foetal immune tolerance, are largely, if not exclusively, responsible for these outcomes. Plasmodial asexual blood stage antigen-specific T cells are detectable in as many as two-thirds of all cord blood samples in malaria-endemic countries of sub-Saharan Africa, indicating that in utero sensitization may be a common phenomenon during pregnancy in these populations. Parasite antigen-specific T cell responses of neonates born to helminth-infected mothers display a highly skewed Th2-type cytokine pattern, with a prominent role for the regulatory cytokine interleukin (IL)-10. Similarly, the cord blood immune response of those born to mothers identified with on-going PAM is characterised by inducible parasite antigen-specific IL-10-producing regulatory T cells that can inhibit both APC HLA expression and Th1-type T cell responses. In contrast, plasmodial antigen-specific Th1-type responses, characterised by IFN-gamma production, predominate in cord blood of those born to mothers successfully treated for Pf malaria during gestation, suggesting that the duration and/or the nature of antigen exposure in utero governs the outcome with respect to neonatal immune responses. Aspects of APC function in the context of these differentially modulated responses, whether and how the latter translate into altered susceptibility to Pf infection during infancy, as well as the possible implications for vaccination in early life, are aspects that are discussed in this review.
Mol Biochem Parasitol 2007 Jan
PMID:Placental Plasmodium falciparum infection: causes and consequences of in utero sensitization to parasite antigens. 1708 34

In infections with Schistosoma mansoni the paired adult worms produce hundreds of eggs daily, of which many get trapped in various organs of the human host. The eggs produce complex and unique protein- and lipid-linked glycans, which are important activators and modulators of the host's immune response. The same parasite-derived glycoconjugates are also attractive immunodiagnostic targets in enzyme-linked immunosorbent assays (ELISAs), which detect circulating antigens in serum or urine of the host. Here, we report for the first time that in addition to glycoprotein and glycolipid antigens, schistosome eggs also excrete unique unconjugated oligosaccharides. Employing the schistosome-specific anti-carbohydrate monoclonal antibody 114-4D12 in an affinity purification approach, a specific set of free oligosaccharides was detected by matrix-assisted laser-desorption-ionisation time-of-flight mass spectrometry (MALDI-TOF MS) in human S. mansoni infection urine as well as in egg-incubation medium, but not in worm-culture medium. Nano-scale reverse-phase liquid chromatography-mass spectrometry (nano-RP-LC-MS) analysis of the purified egg-derived oligosaccharides indicated that the captured compounds form a series of multi-fucosylated multimeric N-acetylhexosamine chains with a non-reducing terminal Fucalpha1-2Fucalpha1-3GalNAcbeta1-4(Fucalpha1-2Fucalpha1-3)GlcNAcbeta1- (DF-LDN-DF) sequence which forms the epitope of mAb 114-4D12. Since fucosylated (egg) glycoconjugates have been shown to harbour immunogenic properties, we anticipate that these unconjugated oligosaccharides also play a role in the immunobiology associated with schistosome eggs. Moreover, our data indicate that mass spectrometric detection of a set of signature molecules in urine has potential as a new approach for the diagnosis of schistosomiasis and possibly other helminth infections.
Mol Biochem Parasitol 2007 Feb
PMID:Schistosoma mansoni eggs excrete specific free oligosaccharides that are detectable in the urine of the human host. 1718 64

In schistosomiasis, a parasitic disease caused by helminths, the parasite eggs induce a T helper 2 cell (T(H)2) response in the host. Here, the specific role of human monocyte-derived dendritic cells (DCs) in initiation and polarization of the egg-specific T cell responses was examined. We demonstrate that immature DCs (iDCs) pulsed with schistosome soluble egg antigens (SEA) do not show an increase in expression of co-stimulatory molecules or cytokines, indicating that no conventional maturation was induced. The ability of SEA to affect the Toll-like receptor (TLR) induced maturation of iDCs was examined by copulsing the DCs with SEA and TLR-ligands. SEA suppressed both the maturation of iDCs induced by poly-I:C and LPS, as indicated by a decrease in co-stimulatory molecule expression and production of IL-12, IL-6 and TNF-alpha. In addition, SEA suppressed T(H)1 responses induced by the poly-I:C-pulsed DCs, and skewed the LPS-induced mixed response towards a T(H)2 response. Immature DCs rapidly internalized SEA through the C-type lectins DC-SIGN, MGL and the mannose receptor and the antigens were targeted to MHC class II-positive lysosomal compartments. The internalization of SEA by multiple C-type lectins may be important to regulate the response of the iDCs to TLR-induced signals.
Mol Immunol 2007 Apr
PMID:Schistosoma mansoni soluble egg antigens are internalized by human dendritic cells through multiple C-type lectins and suppress TLR-induced dendritic cell activation. 1724 63

Parasitic infections, including schistosomiasis, are associated with high titres of specific and non-specific IgE antibody, and many reports show an in vitro role for IgE in parasite killing. Despite an active immune response, schistosomes survive for long periods in the human bloodstream, implying that the parasite is able to overcome or evade the IgE response mounted against it. One such mechanism is through cleavage of IgE into non-functional fragments by potent parasite derived enzymes. Using domain swap antibodies, recombinant Fcepsilon, and C-terminally tagged Cepsilon4 domains, we have narrowed down the principal cleavage sites to the Cepsilon2/Cepsilon3 and Cepsilon3/Cepsilon4 interdomain region of the IgE-Fc. Two serine proteases, one chymotrypsin-like and the second trypsin-like, have been proposed to be involved. Inhibition assays using selective inhibitors confirmed that both proteases contribute to Fc cleavage, although the chymotrypsin-like enzyme makes the greater contribution. Protein sequencing of IgE fragments cleaved by highly pure preparations of the chymotrypsin-like enzyme revealed that cleavage also occurred post Lys residues within kappa light chain dimers (LELK/GA). Related sequences are found in myosin, thrombospondin, collagen and actin-related proteins; macromolecules present in the skin and through which cercariae must penetrate to initiate an infection. Chemical knockout experiments using specific inhibitors and chromogenic substrates allowed us to show that the trypsin-like enzyme was responsible for light chain cleavage. The finding that pathogenic proteases can cleave the Fc of IgE may provide a useful biochemical tool for the further analysis of IgE structure. Indeed, the finding may raise new possibilities for treatment of IgE-mediated allergic reactions mediated through Fcepsilon-receptors.
Mol Immunol 2008 Jan
PMID:Proteases from Schistosoma mansoni cercariae cleave IgE at solvent exposed interdomain regions. 1763 66


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