Pathology Of Schistosomiasis Research Articles

Hepatic Topology of Glycosphingolipids in Schistosoma mansoni-Infected Hamsters.

Schistosomiasis is a neglected tropical disease caused by worm parasites of the genus Schistosoma. Upon infection, parasite eggs can lodge inside of host organs like the liver. This leads to granuloma formation, which is the main cause of the pathology of schistosomiasis. To better understand the different levels of host-pathogen interaction and pathology, our study focused on the characterization of glycosphingolipids (GSLs). For this purpose, GSLs in livers of infected and noninfected hamsters were studied by combining high-spatial-resolution atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI) with nanoscale hydrophilic interaction liquid chromatography tandem mass spectrometry (nano-HILIC MS/MS). Nano-HILIC MS/MS revealed 60 GSL species with a distinct saccharide and ceramide composition. AP-SMALDI MSI measurements were conducted in positive- and negative-ion mode for the visualization of neutral and acidic GSLs. Based on nano-HILIC MS/MS results, we discovered no downregulated but 50 significantly upregulated GSLs in liver samples of infected hamsters. AP-SMALDI MSI showed that 44 of these GSL species were associated with the granulomas in the liver tissue. Our findings suggest an important role of GSLs during granuloma formation.

Synthetic peptides derived from the Schistosoma mansoni secretory protein Sm16 induce contrasting responses in hepatic stellate cells

Sm16 is a 16 KDa protein released by Schistosoma mansoni that modulates inflammatory responses in host cells. Sm16 is expressed by several life cycle stages of S. mansoni, including the egg stage. Schistosome eggs are known to provoke chronic schistosomiasis pathology, which involves the development of liver fibrosis. Hepatic stellate cells (HSCs), which are responsible for this fibrosis, are susceptible to immunomodulation by S. mansoni whole egg secretions. To define the effects of Sm16 exposure on HSCs, two synthetic peptide derivatives of Sm16, coined “KS-84″ and “KS-66″, were tested against LX-2 cells, an immortalised human HSC line, and RNA sequencing was used to assess the transcriptional changes induced by each peptide. In total, 78 and 798 genes were found to be significantly differentially expressed by KS-84 and KS-66 treatment, respectively. In silico pathway analysis of these genes revealed that KS-84 reduced LX-2 cell activation and fibrotic potential, whereas KS-66 increased both processes. Reduced transforming growth factor-β1 (TGF-β1) signalling was identified as a potential mechanism of KS-84-induced inhibition of LX-2 activation. Taken together, these findings indicate a potential role for Sm16 in combatting fibrotic liver disease.

Eosinophils participate in modulation of liver immune response and tissue damage induced by Schistosoma mansoni infection in mice.

The severity of chronic schistosomiasis has been mainly associated with the intensity and extension of the inflammatory response induced by egg-secreted antigens in the host tissue, especially in the liver and intestine. During acute schistosomiasis, eosinophils account for approximately 50% of the cells that compose the liver granulomas; however, the role of this cell-type in the pathology of schistosomiasis remains controversial. In the current study, we compared the parasite burden and liver immunopathological changes during experimental schistosomiasis in wild-type (WT) BALB/c mice and BALB/c mice selectively deficient for the differentiation of eosinophils (ΔdblGATA). Our data demonstrated that the absence of eosinophil differentiation did not alter the S. mansoni load or the liver retention of parasite eggs; however, there were significant changes in the liver immune response profile and tissue damage. S. mansoni infection in ΔdblGATA mice resulted in significantly lower liver concentrations of IL-5, IL-13, IL-33, IL-17, IL-10, and TGF-β and higher concentrations of IFN-γ and TNF-α, as compared to WT mice. The changes in liver immune response observed in infected ΔdblGATA mice were accompanied by lower collagen deposition, but higher liver damage and larger granulomas. Moreover, the absence of eosinophils resulted in a higher mortality rate in mice infected with a high parasite load. Therefore, the data indicated that eosinophils participate in the establishment and/or amplification of liver Th-2 and regulatory response induced by S. mansoni, which is necessary for the balance between liver damage and fibrosis, which in turn is essential for modulating disease severity.

Sodium butyrate ameliorates Schistosoma japonicum-induced liver fibrosis by inhibiting HMGB1 expression

Schistosomiasis is a prevalent zoonotic parasitic disease caused by schistosomes. Its main threat to human health is hepatic granuloma and fibrosis due to worm eggs. Praziquantel remains the first choice for the treatment of schistosomiasis but has limited benefit in treating liver fibrosis. Therefore, the need to develop effective drugs for treating schistosomiasis-induced hepatic fibrosis is urgent. High-mobility group box 1 protein (HMGB1) is a potential immune mediator that is highly associated with the development of some fibrotic diseases and may be involved in the liver pathology of schistosomiasis. We speculated that HMGB1 inhibitors could have an anti-fibrotic effect. Sodium butyrate (SB), a potent inhibitor of HMGB1, has shown anti-inflammatory activity in some animal disease models. In this study, we evaluated the effects of SB on a murine schistosomiasis model. Mice were percutaneously infected with 20 ± 2 cercariae of Schistosoma japonicum. SB (500 mg/kg/day) was administered every 3 days for the entire experiment period. The activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), liver histopathology, HMGB1 expression, and the levels of interferon gamma (IFN-γ), transforming growth factor-β1 (TGF-β1), and interleukin-6 (IL-6) in serum were analyzed. SB reduced hepatic granuloma and fibrosis of schistosomiasis, reflected by the decreased levels of ALT and AST in serum and the reduced expression of pro-inflammatory and fibrogenic cytokines (IFN-γ, TGF-β1, and IL-6). The protective effect could be attributable to the inhibition of the expression of HMGB1 and release by SB.

The effect of fs800 on female egg production in Schistosoma mansoni

During schistosomiasis, the paired Schistosoma mansoni female produces about 300 eggs each day. These eggs are responsible for the clinical picture and the transmission of the disease. During female development and egg production, fs800 is expressed only in female vitelline cells. Blast search of fs800 did not show similarities with any published sequences by NCBI. We hypothesize that the product of this gene plays a role in S. mansoni egg production. By using RNA interference to knockdown fs800 and quantitative PCR to measure the gene expression in the female schistosomes, we were able to demonstrate that fs800 product is crucial for viable egg production, it has no effect on worm health or male-female pairing. Our data suggest fs800 inhibition as a potential target to prevent transmission and pathology of schistosomiasis.

Schistosome eggs stimulate reactive oxygen species production to enhance M2 macrophage differentiation and promote hepatic pathology in schistosomiasis.

Schistosomiasis is a neglected tropical disease of public health concern. The most devastating pathology in schistosomiasis japonica and mansoni is mainly attributed to the egg-induced granulomatous response and secondary fibrosis in host liver, which may lead to portal hypertension or even death of the host. Schistosome eggs induce M2 macrophages-rich granulomas and these M2 macrophages play critical roles in the maintenance of granuloma and subsequent fibrosis. Reactive oxygen species (ROS), which are highly produced by stimulated macrophages during infection and necessary for the differentiation of M2 macrophages, are massively distributed around deposited eggs in the liver. However, whether ROS are induced by schistosome eggs to subsequently promote M2 macrophage differentiation, and the possible underlying mechanisms as well, remain to be clarified during S. japonicum infection. Herein, we observed that extensive expression of ROS in the liver of S. japonicum-infected mice. Injection of ROS inhibitor in infected mice resulted in reduced hepatic granulomatous responses and fibrosis. Further investigations revealed that inhibition of ROS production in S. japonicum-infected mice reduces the differentiation of M2, accompanied by increased M1 macrophage differentiation. Finally, we proved that S. japonicum egg antigens (SEA) induce a high level of ROS production via both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and mitochondria in macrophages. Our study may help to better understand the mechanism of schistosomiasis japonica-induced hepatic pathology and contribute to the development of potential therapeutic strategies by interfering with ROS production.

Modulation of the Host Immune Response by Schistosome Egg-Secreted Proteins Is a Critical Avenue of Host-Parasite Communication.

During a schistosome infection, the interactions that occur between the mammalian host and the parasite change rapidly once egg laying begins. Both juvenile and adult schistosomes adapt to indefinitely avoid the host immune system. In contrast, the survival of eggs relies on quickly traversing from the host. Following the commencement of egg laying, the host immune response undergoes a shift from a type 1 helper (Th1) inflammatory response to a type 2 helper (Th2) granulomatous response. This change is driven by immunomodulatory proteins within the egg excretory/secretory products (ESPs), which interact with host cells and alter their behaviour to promote egg translocation. However, in parallel, these ESPs also provoke the development of chronic schistosomiasis pathology. Recent studies using high-throughput proteomics have begun to characterise the components of schistosome egg ESPs, particularly those of Schistosoma mansoni, S. japonicum and S. haematobium. Future application of this knowledge may lead to the identification of proteins with novel immunomodulatory activity or pathological importance. However, efforts in this area are limited by a lack of in situ or in vivo functional characterisation of these proteins. This review will highlight the current knowledge of the content and demonstrated functions of schistosome egg ESPs.

Schistosomes in the Lung: Immunobiology and Opportunity.

Schistosome infection is a major cause of global morbidity, particularly in sub-Saharan Africa. However, there is no effective vaccine for this major neglected tropical disease, and re-infection routinely occurs after chemotherapeutic treatment. Following invasion through the skin, larval schistosomula enter the circulatory system and migrate through the lung before maturing to adulthood in the mesenteric or urogenital vasculature. Eggs released from adult worms can become trapped in various tissues, with resultant inflammatory responses leading to hepato-splenic, intestinal, or urogenital disease – processes that have been extensively studied in recent years. In contrast, although lung pathology can occur in both the acute and chronic phases of schistosomiasis, the mechanisms underlying pulmonary disease are particularly poorly understood. In chronic infection, egg-mediated fibrosis and vascular destruction can lead to the formation of portosystemic shunts through which eggs can embolise to the lungs, where they can trigger granulomatous disease. Acute schistosomiasis, or Katayama syndrome, which is primarily evident in non-endemic individuals, occurs during pulmonary larval migration, maturation, and initial egg-production, often involving fever and a cough with an accompanying immune cell infiltrate into the lung. Importantly, lung migrating larvae are not just a cause of inflammation and pathology but are a key target for future vaccine design. However, vaccine efforts are hindered by a limited understanding of what constitutes a protective immune response to larvae. In this review, we explore the current understanding of pulmonary immune responses and inflammatory pathology in schistosomiasis, highlighting important unanswered questions and areas for future research.

Schistosomiasis Associated Glomerulopathy (Glomerulonephristis / Nephrotic Syndrome): A review and Update of the Literature

Schistosomiasis may affect a number of organs within the human body. Schistosomiasis may also be associated with glomerular disease of the kidney in the form of glomerulonephritis and nephrotic syndrome. The association between Schistosomiasis and glomerulopathy may not be well known by a number of practitioners and its pathophysiology may not be very well understood and this could be due to the underdiagnosis of the disease due to the possibility of lack of facilities within the Schistosomiasis endemic areas of the world especially within tropical Africa. Nevertheless, there are a number of patterns of renal involvement in Schistosomiasis which include (a) upper urinary tract sequelae of lower urinary tract Schistosomiasis pathology, (b) immune-related glomerulonephritis, (c) as well as oxidant-stress-mediated renal tubular glomerulonephritis. The renal involvement by Schistosomiasis does tend to be ensued by the development of Schistosomiasis-associated Glomerulopathy (Glomerulonephritis / Nephrotic Syndrome) of varying severity. Individuals affected by Schistosomiasis-associated kidney disease may develop (a) asymptomatic disease which tends to related to self-limited and asymptomatic glomerular disease (b) symptomatic disease which most commonly would tend to present with nephrotic syndrome most often in patients who develop hepato-splenic schistosomiasis with liver fibrosis associated with Schistosoma mansoni infection. Symptomatic patients tend to develop severe hypo-proteinemia, half of the patients tend to have elevated blood pressure. In the absence of nephrotic syndrome, patients who have Schistosomiasis-associated glomerulopathy may manifest with: (a) isolated non-nephrotic syndrome proteinuria (b) acute glomerulonephritis associated with haematuria and heavy proteinuria, (c) Nephrotic syndrome together with systemic manifestations of co-infection with salmonella (class II) or hepatitis C virus (Class I), (d) End stage renal disease (ESRD). Some of the patients who have Schistosomiasis of the kidney may present with Haematuria, Hypertension, Hepato-splenic Schistosomiasis. The diagnosis should be suspected with regard to the following scenarios: (a) clinical suspicion in a patient with kidney disease who is known or has been known to have Schistosoma mansoni; (b) exposure to an endemic area, (c) clinical evidence / demonstration of chronic hepatosplenic schistosomiasis, (d) if the patient has not been diagnosed as having been afflicted with schistosomiasis, then schistosomal infection should be documented, (e) majority of patients with schistosomiasis and kidney disease should have kidney biopsy. (f) The patients should be evaluated for co-infection with salmonella, hepatitis C virus, and hepatitis B virus in order to ensure adequate treatment of the disease. Schistosomiasis is the second most devastating tropical parasitic disease globally which tends to be responsible for many urological complications. Nevertheless, glomerular injury is an uncommon complication which has mainly or most often described with Schistosoma Mansoni. When patients who have Schistosomiasis-associated Kidney disease are managed and followed-up on long-term basis with renal end points, one third of the patients independent of the histopathology examination features of the kidney biopsies would tend to progress dialysis. Membranoproliferative glomerulonephritis (MPGN) is an uncommon complication associated with Schistosoma Haematobium infection which tends to be associated with potentially poor prognosis. MPGN could lead quickly to End Stage Renal Disease (ESRD). Anti-helminthic and immunosuppressive medicaments tend not to be effective at advanced stages of the disease and hence efforts need to be focused upon the prevention, early detection, as well as treatment of Schistosoma infections among at-risk groups of individuals. In order to reduce morbidity related to Schistosoma-associated nephropathy, public health policy, should be concentrated upon the prevention of the disease by the control of snail, improved sanitation, and health education, as well as by the implementation, and sustenance of chemotherapy-based control strategies. Considering that many individuals are found yearly to be inflicted by Schistosomiasis who tend to dwell in more rural parts of their countries where facilities for the undertaking of renal function tests and biopsies of the kidney tend not to be readily available, there is the likelihood that Schistosomiasis-associated nephropathies may be highly underdiagnosed globally.

SYNERGY BETWEEN BETA-1, 3-GLUCAN AND PRAZIQUANTEL IN THE TREATMENT OF EXPERIMENTAL CHRONIC SCHISTOSOMIASIS MANSONI

Praziquantel can develop resistance and cannot counteract schistosomiasis pathology. β-glucanwas used as an immunomodulator for innate and acquired immunity. This study evaluated theeffects of β-glucan either alone or with PZQ on chronic Schistosoma mansoni infection. Micewere divided into five groups: uninfected control, infected untreated, PZQ treated, β-glucantreated and combined treatment groups. Treatment started at the end of 8th week P.I. Parasitological,histopathological, immunohistochemical (α-SMA) studies and biochemical assays (Myeloperoxidaseactivity, NO, TNF-α, INF-γ, IL-13 & hydroxyproline) in liver tissues were done.Combination of β-glucan and PZQ therapy resulted in significant decrease in adults count, hepaticegg loads, granuloma number and diameter as well as significant improvement of hepaticpathology and reduction of hepatic fibrosis.

Immunopathology in schistosomiasis is regulated by TLR2,4- and IFN-\u03b3-activated MSC through modulating Th1/Th2 responses

Background and aimsA marked egg-induced CD4+ T cell programmed inflammation and subsequent hepatic fibrosis characterize the pathogenesis of schistosomiasis. Mesenchymal stem cell (MSC) has been extensively studied for the treatment of schistosomiasis. However, the mechanism by which MSCs modulate the pathogenesis of schistosomiasis has not been clarified. Furthermore, the local inflammatory milieu may greatly influence the immunoregulatory properties of MSCs, and our early experiments demonstrated that Toll-like receptor (TLR)2/TLR4 agonist effected immune modulation of MSC. Here, we further investigated their modulation on the pathogenesis of schistosomiasis.MethodsAdult BALB/c male mice were percutaneously infected with 16 ± 2 pairs S. japonicum cercariae and received intravenously pretreated MSC at 1 week and 3 weeks post-infection, respectively. At 8 weeks post-infection, effects of MSC on liver histology were shown by hematoxylin and eosin (H&E) staining and Masson staining and quantitatively compared by the hepatic hydroxyproline content; α-smooth muscle actin (α-SMA), collagen type I(Col-1), transforming growth factor β (TGF-β), and tumor necrosis factor-α (TNF-α) gene expression in the liver were assessed by semi-quantitative polymerase chain reaction (PCR); the Th1/Th2 dominance among different groups was compared by analyzing CD4+ interferon-γ (IFN-γ)+ and CD4+interleukin-4 (IL-4)+T cells in the liver by flow cytometry and serum level of IFN-γ and IL-5 using enzyme-linked immunosorbent assay (ELISA). Effects of different kinds of MSC were further evaluated in vitro by the coculture system.ResultsResults showed TLR4- and IFN-γ-activated MSC alleviated liver fibrosis in infected mice, without a significant increase of mortality, and unpretreated MSC showed no clear improvement; however, TLR2- and IFN-γ-activated MSC displayed aggravated immunopathology. In accord with the pathological results, TLR4- and IFN-γ-activated MSC groups showed moderate enhancement of Th1 response in vitro and clear Th1 dominance in vivo without leading to extreme inflammation, whereas TLR2- and IFN-γ-activated MSC not only induced Th1 response, but also triggered excessive inflammation as evidenced by atrophy of the thymus and higher TNF level in the coculture system.ConclusionsThis study demonstrates that TLR4 combined with IFN-γ can activate the MSC group with positive effects on the pathology of schistosomiasis by modulating Th subsets at some degree. This result suggests that when MSC is being used to treat different immuno-disturbance complications, subtle pretreatment methods should be seriously considered.

Antiparasitic activity of piplartine (piperlongumine) in a mouse model of schistosomiasis

Schistosomiasis is one of the most important parasitic infections in terms of its negative effects on public health and economics. Since praziquantel is currently the only drug available to treat schistosomiasis, there is an urgent need to identify new anthelmintic agents. Piplartine, also known as piperlongumine, is a biologically active alkaloid/amide from peppers that can be detected in high amounts in the roots of Piper tuberculatum. Previously, it has been shown to have in vitro schistosomicidal effects. However, its anthelmintic activity in an animal host has not been reported. In the present work, in vivo antischistosomal properties of isolated piplartine were evaluated in a mouse model of schistosomiasis infected with either adult (patent infection) or juvenile (pre-patent infection) stages of Schistosoma mansoni. A single dose of piplartine (100, 200 or 400 mg/kg) or daily doses for five consecutive days (100 mg/kg/day) administered orally to mice infected with schistosomes resulted in a reduction in worm burden and egg production. Treatment with the highest piplartine dose (400 mg/kg) caused a significant reduction in a total worm burden of 60.4% (P < 0.001) in mice harbouring adult parasites. S. mansoni egg production, a process responsible for pathology in schistosomiasis, was also significantly inhibited by piplartine. Studies using scanning electron microscopy revealed substantial tegumental alterations in parasites recovered from mice. Since piplartine has well-characterized mechanisms of toxicity, is easily available, and is cost-effective, our results indicate that this bioactive molecule derived from medicinal plants could be a potential lead compound for novel antischistosomal agents.

Follicular helper T cells recruit eosinophils into host liver by producing CXCL12 during Schistosoma japonicum infection.

Schistosomiasis affects at least 200 million people in tropical and subtropical areas. The major pathology of schistosomiasis is egg‐induced liver granuloma characterized by an eosinophil‐rich inflammatory infiltration around the eggs, which subsequently leads to hepatic fibrosis and circulatory impairment in host. However, the mechanisms how eosinophils are recruited into the liver, which are crucial for the better understanding of the mechanisms underlying granuloma formation and control of schistosomiasis, remain unclear. In this study, we showed that follicular helper T (Tfh) cells participate in recruitment of eosinophils into liver partially by producing CXCL12 during schistosome infection. Our findings uncovered a previously unappreciated role of Tfh cells in promotion of the development of liver granuloma in schistosomiasis, making Tfh‐CXCL12‐eosinophil axis a potential target for intervention of schistosomiasis.

Strongyloides venezuelensis-infection alters the profile of cytokines and liver inflammation in mice co-infected with Schistosoma mansoni

Human co-infection by helminth species is frequent, but their consequences are mostly unknown. Here, we investigate the impact of Strongyloides venezuelensis co-infection on the immune response, schistosome burden, and the associated pathology of schistosomiasis in mice. Co-infection did not alter the schistosome parasite burden, but reduced the IL-4/IL-10 ratio during acute schistosomiasis, indicating induction of modulatory mechanisms. Simultaneous infection with S. venezuelensis and S. mansoni increased the liver concentration of IFN-γ and altered the Th2/Th1 balance, leading to great infiltration of neutrophils and macrophages, which resulted in larger liver inflammation and increased serum transaminase activity in comparison with mono-infected mice. Mice infected with S. venezuelensis at two and four weeks after S. mansoni infection showed significant increase of Th1/Th2/Th17/Treg cytokines and strong cellular infiltration in the liver in comparison with mono-infected mice. However, only in mice co-infected after two weeks of schistosomiasis, the liver immune response leads to more intense Th2 polarization, increased liver inflammation, and transaminase serum activity. S. venezuelensis co-infection during chronic schistosomiasis did not significantly alter liver inflammation. Therefore, S. venezuelensis co-infection affects the host immune responses and morbidity of schistosomiasis, but the effects largely depend on the stage of the S. mansoni infection.

The C-type Lectin Receptor-Driven, Th17 Cell-Mediated Severe Pathology in Schistosomiasis: Not All Immune Responses to Helminth Parasites Are Th2 Dominated.

Schistosomiasis is a major helminthic disease in which damage to the affected organs is orchestrated by a pathogenic host CD4 T helper (Th) cell-mediated immune response against parasite eggs. In the case of the species Schistosoma mansoni, the resulting granulomatous inflammation and fibrosis takes place in the liver and intestines. The magnitude of disease varies greatly from individual to individual but in a minority of patients, there is severe disease and death. S. mansoni infection in a murine model similarly results in marked strain variation of immunopathology. In the most commonly examined mouse strain, C57BL/6 (BL/6), there is relatively mild hepatic pathology arising in a Th2-dominated cytokine environment. In contrast, CBA mice develop decisively more severe lesions largely driven by proinflammatory IL-17-producing Th17 cells. Dendritic cells (DCs) from CBA mice differ sharply with those from BL/6 mice in that they vastly over-express the C-type lectin receptor (CLR) CD209a (SIGNR5), a homolog of human DC-SIGN, which senses glycans such as those produced by schistosome eggs. Silencing of CD209a, and recent studies with CD209a KO CBA mice have shown that this receptor is crucial to induce the pathogenic Th17 cell response; indeed, CD209a KO mice display markedly reduced immunopathology akin to that seen in BL/6 mice. Mechanistically, CD209a synergizes with the related CLRs Dectin-2 and Mincle to stimulate increased DC production of IL-1β and IL-23, necessary for pathogenic Th17 cell development. These findings denote key molecular underpinnings of disease variability based on selection and function of contrasting Th cell subsets.

An Abies procera-derived tetracyclic triterpene containing a steroid-like nucleus core and a lactone side chain attenuates in vitro survival of both Fasciola hepatica and Schistosoma mansoni

Two economically and biomedically important platyhelminth species, Fasciola hepatica (liver fluke) and Schistosoma mansoni (blood fluke), are responsible for the neglected tropical diseases (NTDs) fasciolosis and schistosomiasis. Due to the absence of prophylactic vaccines, these NTDs are principally managed by the single class chemotherapies triclabendazole (F. hepatica) and praziquantel (S. mansoni). Unfortunately, liver fluke resistance to triclabendazole has been widely reported and blood fluke insensitivity/resistance to praziquantel has been observed in both laboratory settings as well as in endemic communities. Therefore, the identification of new anthelmintics is necessary for the sustainable control of these NTDs in both animal and human populations. Here, continuing our work with phytochemicals, we isolated ten triterpenoids from the mature bark of Abies species and assessed their anthelmintic activities against F. hepatica and S. mansoni larval and adult lifecycle stages. Full 1H and 13C NMR-mediated structural elucidation of the two most active triterpenoids revealed that a tetracyclic steroid-like nucleus core and a lactone side chain are associated with the observed anthelmintic effects. When compared to representative mammalian cell lines (MDBK and HepG2), the most potent triterpenoid (700015; anthelmintic EC50s range from 0.7 μM–15.6 μM) displayed anthelmintic selectivity (selectivity indices for F. hepatica: 13 for newly excysted juveniles, 46 for immature flukes, 2 for mature flukes; selectivity indices for S. mansoni: 14 for schistosomula, 9 for immature flukes, 4 for adult males and 3 for adult females) and induced severe disruption of surface membranes in both liver and blood flukes. S. mansoni egg production, a process responsible for pathology in schistosomiasis, was also severely inhibited by 700015. Together, our results describe the structural elucidation of a novel broad acting anthelmintic triterpenoid and support further investigations developing this compound into more potent analogues for the control of both fasciolosis and schistosomiasis.

Treg/Th17 balance and immunology of schistosome infection: a review

Many factors are reported to be involved in regulating the immunopathogenesis of schistosome infection. CD4+ T cell is one of the key players in the regulation of the liver granuloma formation by differentiation into different effector subsets including T helper (Th) 1, Th2, Th17, and T regulatory cells (Treg cells). Treg cells play an important suppressive role in immunopathology control and favor the pathogen to escape from the host immune assault. The functional activity of Tregs has been related to some autoimmune diseases including asthma and inflammatory bowel disease, which suggests that the manipulation of Tregs to restore their numbers and function may be therapeutic. However, interleukin-17 (IL-17) is a pro-inflammatory cytokine involved in the pathogenesis of many inflammatory and infectious conditions, including schistosomiasis. Therefore, a deeper understanding of the mechanisms of these immune regulations is necessary for the better control of pathology in schistosomiasis. In this paper, we review the Treg/Th17 balance and the immunology of schistosome infection.

Schistosomiasis: Review of an immune complex disease

BACKGROUND: Morbidity due to human schistosomiasis is associated with host immune responses which result in immune based inflammation, granuloma formation and fibrotic lesions.&#x0D; MATERIALS AND METHODS: This is a review of the literature on the immunology of schistosomiasis and the description of the immunopathogenesis of the disease. Relevant articles were retrieved using electronic search and hand search of published literature.&#x0D; RESULTS: Host responses which include immune based inflammation, granuloma formation and fibrotic lesions are aimed at destroying schistosome ova lodged in the liver, intestinal and bladder walls, and other tissues. At the site of the infection, ‘swimmers’ itch is due to physical damage to the skin by proteases and other toxic substances secreted by cercaria. During intestinal Schistosomiasis, the parasitic ova are lodged in the liver provoking fibrogenesis, while during urinary schistosomiasis pathology is attributed to the formation of granuloma along the urinary tract, there is fibrosis which lead to strictures, calcification and urodynamic abnormalities. The classic descriptions of schistosomiasis-related morbidity focus on pathologies unique to schistosome infection: periportal fibrosis for intestinal schistosomiasis and bladder deformity and hydronephrosis for urogenital schistosomiasis.&#x0D; CONCLUSION: This review provides some useful information concerning some aspects of the relationships between Schistosoma species and the human host.

Proteomic and immunomic analysis of Schistosoma mekongi egg proteins

Schistosomiasis remains a global health problem. In the Mekong river basin, approximately 80,000 people are at risk of infection by Schistosoma mekongi. The parasite's eggs become entrapped in the host's organs and induce massive inflammation, contributing to the pathogenesis of schistosomiasis. In addition, egg antigens are important in circumoval precipitin tests (COPTs) and other diagnostic techniques. Little is known regarding the egg proteins of S. mekongi, and so we applied immunoblotting and mass spectrometry-based proteomic approaches to study these proteins and their antigenicity. A total of 360 unique proteins were identified in S. mekongi eggs using proteomic analyses. The major protein components of S. mekongi eggs were classified into several groups by functions, including proteins of unknown function, structural proteins, and regulators of transcription and translation. The most abundant proteins in S. mekongi eggs were antioxidant proteins, potentially reflecting the need to neutralize reactive oxidative species released from host immune cells. Immunomic analyses revealed that only DNA replication factor Cdt1 and heat shock protein 70 overlap between the proteins recognized by sera of infected mice and humans, illustrating the challenges of knowledge transfer from animal models to human patients. Forty-one immunoreactive protein bands were recognized by either mouse or patient sera. Phosphoglycerate kinase, fructose-1,6-bisphosphate aldolase and elongation factor 1 appeared to be interesting immunogens of S. mekongi eggs as these proteins were recognized by polyclonal IgMs and IgGs in patient sera. Our findings provide new information on the protein composition of S. mekongi eggs as well as the beginnings of a S. mekongi immunogen dataset. These data may help us better understand the pathology of schistosomiasis as well as natural antibody responses against S. mekongi egg proteins, both of which may be useful in including S. mekongi to other schistosoma diagnostic, vaccine and immunotherapy development.

Utilization of real time PCR for the assessment of egg burden in the organs of Schistosoma japonicum experimentally infected mice

Schistosoma japonicum, causing zoonotic intestinal schistosomiasis, is found in China, the Philippines and parts of Indonesia. Severe disease manifestations are basically due to the deposition of eggs in some vital organs such as the liver, spleen and brain. Traditionally, histopathological microscopic examination of the egg burden was used to evaluate the intensity of infection in the affected organs. However, this technique is laborious, time-consuming and requires trained personnel. In this study, real time PCR targeting the mitochondrial NADH dehydrogenase I gene was used to compare with microscopic examination of tissue sections in evaluating the egg burdens in different affected organs. Livers, spleens and brains of the S. japonicum infected mice after 8 and 18 weeks post-infection (p.i) were harvested and examined. Results showed that there were statistically significant correlations between the egg burden evaluated by tissue section examination, and the Ct values of the real time PCR of livers with heavy egg burden at 8 (r = −0.81) and 18 (r = −0.80) weeks p.i. Furthermore, a correlation (r = −0.56) between the egg burden assessed by the microscopic examination and Ct value of the real time PCR of spleens with moderate egg burden after 18 weeks p.i and not 8 weeks p.i was also observed. Brains with low egg burden showed no schistosome eggs in the microscopic examination, however one sample tested positive by real time PCR. These results suggested that real time PCR is useful in evaluating schistosome egg burden in the organs of the experimentally infected mice model that will give further insights into the pathology of schistosomiasis.