Pathogenesis Of Schistosomiasis Research Articles

Immunopathogenesis of human schistosomiasis

Schistosomiasis continues to be a significant cause of parasitic morbidity and mortality worldwide. This review considers the basic features of the pathology and clinical outcomes of hepatointestinal and genitourinary schistosomiasis, presents an overview of the numerous studies on animal models that have clarified many of the immunopathological features, and provides insight into our current understanding of the immunopathogenesis and genetic control of human schistosomiasis. In murine schistosomiasis, pathology is induced by a CD4(+) Th2 driven granulomatous response directed against schistosome eggs lodged in the host liver. The Th2 cytokines IL-4 and IL-13 drive this response, whereas IL-10, IL13Ralpha2, IFN-gamma and a subset of regulatory T-cells act to limit schistosome induced pathology. A variety of cell types including hepatic stellate cells, alternatively activated macrophages and regulatory T-cells have also been implicated in the pathogenesis of schistosomiasis. Current knowledge suggests the immunopathogenic mechanisms underlying human schistosomiasis are likely to be similar. The review also considers the future development of anti-pathology schistosome vaccines. As fibrosis is an important feature of many other diseases such as Crohn's disease and sarcoidosis, a comprehensive understanding of the cellular and molecular mechanisms involved in schistosomiasis may also ultimately contribute to the development an effective disease intervention strategy for other granulofibrotic diseases.

Schistosoma mansoni: Microarray analysis of gene expression induced by host sex

Schistosoma mansoni is a digenetic trematode and a human parasite responsible for high social and economic impact. Although some authors have studied the effect of host hormones on parasites, not much is known about the effects of host sex on gene expression in Schistosomes. In order to study gene transcripts associated with the host sex, we compared the gene expression profiles of both male and female unisexual adult S. mansoni parasites raised on either male or female hosts, using DNA microarrays. Our results show that host sex caused differential expression of at least 11 genes in female parasites and of 134 in male parasites. Of the differentially expressed genes in female worms, 10 were preferentially expressed in female worms from male mice, while of the 134 differentially expressed genes in male parasites, 79 (59%) were preferentially expressed in worms from female mice. Further investigation of the role of each of those genes will help understand better their importance in the pathogenesis of Schistosomiasis.

IgG subclasses in human chronic schistosomiasis: over-production of schistosome-specific and non-specific IgG4

IgG subclasses were determined quantitatively in sera from 63 Egyptian men who were infected with Schistosoma mansoni. Total and antigen-specific IgG was measured pre- and post-treatment. Total IgG subclass antibodies were determined by immunoradiometric assay (IRMA) using monoclonal antibodies (MoAbs). The anti-worm and anti-egg specific S. mansoni IgG subclass antibodies were quantitatively measured by ELISA using specific MoAbs and standards obtained by affinity chromatography. Our data show that total IgG of the patients was elevated in the range of two to three times above normal. The magnitude of increase differed markedly among the four subclasses of IgG. The IgG1, IgG2 and IgG3 concentrations were approximately two to four times higher than normal, whereas the IgG4 concentrations was 20 times normal (9000 mg/l). IgG1 and IgG4 tended to dominate the IgG subclass distribution of anti-soluble worm antigen preparation (SWAP) antibodies followed by IgG2 and IgG3. On the other hand, IgG1 and IgG2 dominated the IgG subclass distribution of anti-soluble egg antigen (SEA) antibodies. As with IgG1, IgG2 and IgG3, most IgG4 was non-specific. The role of IgG subclasses in the pathogenesis of schistosomiasis is not clear. However, the high concentration of IgG4 might act as IgE blocking antibody, possibly as anti-idiotypes that may play a role in down-regulation of the immune system when it is challenged with an excess of antigen.

Isolation of the cDNAs encoding secreted and membrane binding proteins from egg of Schistosoma japonicum (Chinese strain)

AbstractThe granulomatous reaction which occurs around egg trapped in the intrahepatic venules ultimately may lead to fibrosis, which is the main pathogenesis of schistosomiasis. The excreted proteins from eggs play an important role during this process, and they may be a target for developing new strategies to control the hepatic pathogenesis caused by schistosome infection. In this study, fifteen genes encoding secreted or membrane binding protein were identified with the signal sequence trapping method by retrovirus mediated expression screening (SST-REX) of cDNAs from the egg of Schistosoma japonicum (Chinese strain).

Identification of hydroxyeicosatetraenoic acid components of schistosomal hemozoin

During the late stages of Schistosoma mansoni infection, adult schistosomes catabolize host erythrocytic hemoglobin. In order to evade the toxic effects of free heme, the blood fluke biomineralizes dimeric heme into an inert crystalline pigment called hemozoin. In the present study, the chemical reactivity of schistosomal hemozoin ( SmHz) toward lipid oxidation was examined, and the biological consequences of reactivity were investigated. Mass spectrometric analysis of polar lipid content associated with SmHz identified a variety of primary and secondary polyunsaturated fatty acid oxidation products, including hydroxyeicosatetraenoic acids. Furthermore, RAW 264.7 macrophage-like cells challenged with lipopolysaccharide prior to phagocytosis of SmHz experienced a decrease in nitric oxide production as compared to control experiments. The presence of these biologically active oxidation products suggests native SmHz is capable of modulating the innate immune response and may play a potential role in the pathogenesis of schistosomiasis.

Schistosoma mansoni: the effect of adrenalectomy on the murine model

Adrenal steroid hormones have been implicated, among others, as one of the most important host factors controlling the onset, establishment, and pathogenesis of schistosomiasis. They appear to inhibit oviposition by Schistosoma mansoni both in vitro and in vivo, and their effect is greatly enhanced when administered in combination with a schistosomicidal drug. Therefore, we hypothesized that adrenalectomy would greatly affect the course of the murine schistosomiasis infection. To test this hypothesis, adrenalectomized mice (Adx) infected with S. mansoni were compared with intact infected and sham-infected controls concerning their mortality rate, numbers of male and female worms, number of eggs, and liver pathology. Compared with controls, Adx infected mice showed an increase of 50% in the mortality rate, as well as 1.7–3 times as many adult worms and twice as many ova per worm pair in their liver. Thus, for the first time, there is evidence that lack of adrenal steroids mediate an increment of the adult worm burden and promote worm fecundity in vivo. The present work was done to test the hypothesis that lack of adrenal steroids enhances adult worm attrition, possibly by their direct effect on the parasite, and by upregulating or downregulating innate and adaptive immune responses.

The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells.

IL-10 reduces immunopathology in many persistent infections, yet the contribution of IL-10 from distinct cellular sources remains poorly defined. We generated IL-10/recombination-activating gene (RAG)2-deficient mice and dissected the role of T cell- and non-T cell-derived IL-10 in schistosomiasis by performing adoptive transfers. In this study, we show that IL-10 is generated by both the innate and adaptive immune response following infection, with both sources regulating the development of type-2 immunity, immune-mediated pathology, and survival of the infected host. Importantly, most of the CD4(+) T cell-produced IL-10 was confined to a subset of T cells expressing CD25. These cells were isolated from egg-induced granulomas and exhibited potent suppressive activity in vitro. Nevertheless, when naive, naturally occurring CD4(+)CD25(+) cells were depleted in adoptive transfers, recipient IL-10/RAG2-deficient animals were more susceptible than RAG2-deficient mice, confirming an additional host-protective role for non-T cell-derived IL-10. Thus, innate effectors and regulatory T cells producing IL-10 cooperate to reduce morbidity and prolong survival in schistosomiasis.

Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism.

Type 2 cytokines regulate fibrotic liver pathology in mice infected with Schistosoma mansoni. Switching the immune response to a type 1-dominant reaction has proven highly effective at reducing the pathologic response. Activation of NOS-2 is critical, because type 1-deviated/NO synthase 2 (NOS-2)-deficient mice completely fail to control their response. Here, we demonstrate the differential regulation of NOS-2 and arginase type 1 (Arg-1) by type 1/type 2 cytokines in vivo and for the first time show a critical role for arginase in the pathogenesis of schistosomiasis. Using cytokine-deficient mice and two granuloma models, we show that induction of Arg-1 is type 2 cytokine dependent. Schistosome eggs induce Arg-1, while Mycobacterium avium-infected mice develop a dominant NOS-2 response. IFN-gamma suppresses Arg-1 activity, because type 1 polarized IL-4/IL-10-deficient, IL-4/IL-13-deficient, and egg/IL-12-sensitized animals fail to up-regulate Arg-1 following egg exposure. Notably, granuloma size decreases in these type-1-deviated/Arg-1-unresponsive mice, suggesting an important regulatory role for Arg-1 in schistosome egg-induced pathology. To test this hypothesis, we administered difluoromethylornithine to block ornithine-aminodecarboxylase, which uses the product of arginine metabolism, L-ornithine, to generate polyamines. Strikingly, granuloma size and hepatic fibrosis increased in the ornithine-aminodecarboxylase-inhibited mice. Furthermore, we show that type 2 cytokine-stimulated macrophages produce proline under strict arginase control. Together, these data reveal an important regulatory role for the arginase biosynthetic pathway in the regulation of inflammation and demonstrate that differential activation of Arg-1/NOS-2 is a critical determinant in the pathogenesis of granuloma formation.

Fucosyltransferases in Schistosoma mansoni development.

Glycoconjugate-bound fucose, abundant in the parasite Schistosoma mansoni, has been found in the form of Fucalpha1,3GlcNAc, Fucalpha1,2Fuc, Fucalpha1,6GlcNAc, and perhaps Fucalpha1,4GlcNAc linkages. Here we quantify fucosyltransferase activities in three developmental stages of S. mansoni. Assays were performed using fluorophore-assisted carbohydrate electrophoresis with detection of radioactive fucose incorporation from GDP-[(14)C]-fucose into structurally defined acceptors. The total fucosyltransferase-specific activity in egg extracts was 50-fold higher than that in the other life stages tested (cercaria and adult worms). A fucosyltransferase was detected that transferred fucose to type-2 oligosaccharides (Galbeta1,4GlcNAc-R), both sialylated (with the sialic acid attached to the terminal Gal by alpha2,3 or 2,6 linkage) and nonsialylated. Another fucosyltransferase was identified that transferred fucose to lactose-based and type-2 fucosylated oligosaccharides, such as LNFIII (Galbeta1,4(Fucalpha1,3)GlcNAcbeta1,3Galbeta1,4Glc). A low level of fucosyltransferase that transfers fucose to no-sialylated type-1 oligosaccharides (Galbeta1,3GlcNAc-R) was also detected. These studies revealed multifucosylated products of the reactions. In addition, the effects of fucose-type iminosugars inhibitors were tested on schistosome fucosyltransferases. A new fucose-type 1-N-iminosugar was four- to sixfold more potent as an inhibitor of schistosome fucosyltransferases in vitro than was deoxyfuconojirimycin. In vivo, this novel 1-iminosugar blocked the expression of a fucosylated epitope (mAb 128C3/3 antigen) that is associated with the pathogenesis of schistosomiasis.

An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response.

In schistosomiasis, chronic parasite egg-induced granuloma formation can lead to tissue destruction and fibrosis, which causes much of the morbidity and mortality associated with this disease. Here we show the importance of IL-13 in the pathogenesis of schistosomiasis, and demonstrate, perhaps for the first time, the therapeutic efficacy of an IL-13 inhibitor, sIL-13Ralpha2-Fc, in the control of hepatic fibrosis. T-helper type 2 (Th2) cytokines dominate the immune response in mice infected with Schistosoma mansoni, yet the specific contributions of IL-13 and IL-4 to the development of fibrosis were not previously investigated. Our studies demonstrate that both cytokines play redundant roles in granuloma formation, which explains the ability of IL-4-deficient mice to form granulomas around eggs. More importantly, however, these studies demonstrate that IL-13 is the dominant Th2-type cytokine regulating fibrosis. IL-13 stimulated collagen production in fibroblasts, and procollagen I and procollagen III mRNA expression was decreased in sIL-13Ralpha2-Fc-treated mice. Moreover, the reduction in fibrosis observed in IL-4-deficient mice was much less pronounced than that in sIL-13Ralpha2-Fc-treated animals. Fibrosis is a major pathological manifestation of a number of allergic, autoimmune, and infectious diseases. Thus, our findings provide evidence that IL-13 inhibitors may be of general therapeutic benefit in preventing damaging tissue fibrosis resulting from Th2-dominated inflammatory responses.

Expression of class II, but not class I, major histocompatibility complex molecules is required for granuloma formation in infection with Schistosoma mansoni.

Previous studies have suggested that granulomatous inflammation in schistosomiasis is mediated by CD4+ T helper lymphocytes sensitized to parasite egg antigens. However, CD8+ T cells have also frequently been associated with the immune response to schistosome eggs. To examine more precisely the role of CD4+ and CD8+ T cells in the pathology of the schistosomal infection, we used mice with targeted mutations in major histocompatibility complex (MHC) class II or class I molecules. These mutations lead, respectively, to the virtual absence of CD4+ and CD8+ T cells. The results clearly show that schistosome-infected MHC class II mutant mice failed to form granulomas around parasite eggs. In contrast, infected MHC class I mutant mice displayed characteristic granulomatous lesions that were comparable to those in wild-type control mice. Moreover, lymphoid cells from MHC class II mutant mice were unable to react to egg antigens with either proliferative or cytokine [interferon-gamma, interleukin (IL)-4, IL-10] responses; nor were they able to present egg antigens to specifically sensitized CD4+ T helper cells from infected syngeneic control mice. By comparison, cells from MHC class I mutant mice exercised all these functions in a manner comparable with those from wild-type controls. These observations clearly demonstrate that schistosomal egg granulomas are mediated by MHC class II-restricted CD4+ T helper cells. They also suggest that CD8+ T cells do not become sensitized to egg antigens and play little role, if any, in the pathogenesis of schistosomiasis.

Experimental murine schistosomiasis: reduced hepatic morbidity after pre- and/or post-infection treatment with ibuprofen or diclofenac sodium.

Arachidonic-acid metabolites appear to participate in skin penetration by and transformation of schistosome cercariae and in the pathogenesis of schistosomiasis. With this in mind, mice were treated with one of two cyclooxygenase inhibitors before and/or after infection with Schistosoma mansoni. The effects of the treatment on liver morbidity and the parasitic infection were then evaluated, using infected, untreated and uninfected, treated mice as controls. Treatment with ibuprofen (20 mg/kg.day) or diclofenac sodium (2.5 mg/kg.day) for 7 days before infection led to significantly lower liver weights, worm loads and hepatic hydroxyproline contents than in the untreated mice. If treatment with either drug was continued after infection, for 28 days, there was an additional significant decrease in hepatic gamma-glutamyl transpeptidase activity. All these parameters except liver weight were similarly affected when treatment with either drug was begun on the day of infection and continued for 28 days. There was no significant change in liver weight or worm load when treatment was delayed until day 28 post-infection but faecal egg counts were reduced in the treated groups. In additional experiments, using a smaller dose of diclofenac sodium (1.25 mg/kg.day), all the measured parameters of infection were significantly decreased when the treatment was initiated 7 days before infection and continued until day 28 post-infection. The results indicate that the treatment of S. mansoni-infected mice with ibuprofen or diclofenac sodium was effective in reducing the severity of infection and in attenuating hepatic fibrosis, particularly when the treatment was started early in relation to the time of infection.

Immunopathology of schistosomiasis in athymic mice.

EOSINOPHILIA—tissue eosinophil infiltrates—granuloma and IgE formation are associated with helminth infections. Eosinophils phagocytose antigen-antibody complexes, neutralise histamine and serotonin, mediate inflammatory reactions and modify delayed hypersensitivity1. The tissue-invasive stage of some parasitic infections provides suitable antigen and stimulates the production of IgE, which in turn induce eosinophilotaxis. We have investigated the need of T-cell participation in the eosinophil response, IgE formation and granuloma formation in schistosomiasis in con-genitally athymic mice which have profound deficiency in T-cell dependent immune response. We looked in particular at eggs as they are important in the pathogenesis of schistosomiasis. They are trapped in tissues and induce chronic granulomatous inflammation with numerous eosinophils. Warren et al.2–6 reported that egg granuloma is a cell-mediated hypersensitivity reaction and it is significantly altered in immunosuppressed mice.

Pathophysiology of ovine schistosomiasis: IV. Effects of experimental Schistosoma mattheei infection on the nitrogen status and digestive efficiency of the host

Measurements of nitrogen balance and apparent digestibility coefficients of various dietary components were made over a 12 week period on 4 sheep exposed 4 weeks previously to 10 000 Schistosoma mattheei cercariae and 4 pair-fed controls. Following the onset of oviposition, the nitrogen status of both groups decreased due to loss of appetite by the infected animals and consequential restriction of dietary intake enforced on the controls. Whereas the controls generally maintained small positive nitrogen balances throughout the study, prolonged periods of negative balance occurred in 3 of the infected sheep; the 4th animal, although in positive balance, also showed a greater depletion of body nitrogen than its control partner. These differences were attributable to greater urinary and faecal losses of nitrogen associated with the disease. The magnitude of the decline in nitrogen balance correlated closely with the severity of other parameters of the disease, such as diarrhoea, weight loss, and hypercatabolism of albumin. The reduced apparent digestibility coefficients of all dietary constituents measured, especially nitrogen, could also be due to the presence of ova in the gastro-intestinal tract. While not providing a direct measure of digestive efficiency, the data presented support the view that impaired digestion and/or malabsorption plays some part in the pathogenesis of schistosomiasis in sheep.

Schistosomiasis and immunologic manifestations

SummaryDescription of a case of Schistosoma Intercalation schistosomiasis in which severe hepatic fibrosis was associated with haemolytic anemia. The presence of cold agglutinins and of other unusual antibodies could be demonstrated. This observation favours the role of immune mechanisms in the pathogenesis of schistosomiasis.