Pathogenesis Of Schistosomiasis Research Articles

An overview of qualitative and quantitative platelet abnormalities in schistosomiasis.

Schistosomiasis is a neglected tropical disease referring to the infection with blood parasitic trematodes of the genus Schistosoma. It impacts millions of people worldwide, primarily in low-to-middle-income countries. Patients infected with schistosomiasis often exhibit a distinct hematological profile, including anemia, eosinophilia, thrombocytopenia, and coagulopathy. Platelets, essential components of the hemostatic system, play a crucial role in the pathogenesis of schistosomiasis. Schistosomes secrete serine proteases and express ectoenzymes, such as calpain protease, alkaline phosphatase (SmAP), phosphodiesterase (SmNPP5), ATP diphosphohydrolase (SmATPDase1), serine protease Sk1, SmSP2, and Sm22.6, which can interfere with platelet normal functioning. This report provides comprehensive, up-to-date information on platelet abnormalities observed in patients with schistosomiasis, highlighting their importance in the disease progression and complications. It delves into the interactions between platelets and schistosomes, including the impact of platelet dysfunction on hemostasis and immune responses, immune-mediated platelet destruction, and the potential mechanisms by which schistosome tegumental ectoenzymes affect platelets. Furthermore, the report clarifies the relationship between platelet abnormalities and clinical manifestations such as thrombocytopenia, coagulation disorders, and the emergence of portal hypertension and gastrointestinal bleeding. Understanding the complex interplay between platelets and schistosomes is crucial for improving patient management and outcomes in schistosomiasis, particularly for those with platelet alterations. This knowledge contributes to improved diagnostic methods, innovative treatment strategies, and global efforts to control and eliminate schistosomiasis.

Rhodopsin orphan GPCR20 interacts with neuropeptides and directs growth, sexual differentiation, and egg production in female Schistosoma mansoni.

Schistosomes cause schistosomiasis, one of the neglected tropical diseases as defined by the WHO. For decades, the treatment of schistosomiasis relies on a single drug, praziquantel. Due to its wide use, there is justified fear of resistance against this drug, and a vaccine is not available. Besides its biological relevance in signal transduction processes, the class of G protein-coupled receptors (GPCRs) is also well suited for drug design. Against this background, we characterized one GPCR of Schistosoma mansoni, SmGPCR20, at the molecular and functional level. We identified two potential neuropeptides (NPPs) as ligands, SmNPP26 and SmNPP40, and unraveled their roles, in combination with SmGPCR20, in neuronal processes controlling egg production, oogenesis, and growth of S. mansoni females. Since eggs are closely associated with the pathogenesis of schistosomiasis, our results contribute to the understanding of processes leading to egg production in schistosomes, which is under the control of pairing in this exceptional parasite.

Clustered Regularly Interspaced Short Palindromic Repeats/ CRISPR associated protein 9-mediated editing of Schistosoma mansoni genes: Identifying genes for immunologically potent drug and vaccine development.

ABSTRACT Schistosomiasis is a neglected acute and chronic tropical disease caused by intestinal (Schistosoma mansoni and Schistosoma japonicum) and urogenital (Schistosoma haematobium) helminth parasites (blood flukes or digenetic trematodes). It afflicts over 250 million people worldwide, the majority of whom reside in impoverished tropical and subtropical regions in sub-Saharan Africa. Schistosomiasis is the second most common devastating parasitic disease in the world after malaria and causes over 200,000 deaths annually. Currently, there is no effective and approved vaccine available for human use, and treatment strongly relies on praziquantel drug therapy, which is ineffective in killing immature larval schistosomula stages and eggs already lodged in the tissues. The Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9 (CRISPR/Cas9)-mediated gene editing tool is used to deactivate a gene of interest to scrutinize its role in health and disease, and to identify genes for vaccine and drug targeting. The present review aims to summarize the major findings from the current literature reporting the usage of CRISPR/Cas9-mediated gene editing to inactivate genes in S. mansoni (acetylcholinesterase (AChE), T2 ribonuclease omega-1 (ω1), sulfotransferase oxamniquine resistance protein (SULT-OR), and α-N-acetylgalactosaminidase (SmNAGAL)), and freshwater gastropod snails, Biomphalaria glabrata (allograft inflammatory factor (BgAIF)), an obligatory component of the life cycle of S. mansoni, to identify their roles in the pathogenesis of schistosomiasis, and to highlight the importance of such studies in identifying and developing drugs and vaccines with high therapeutic efficacy.

Understanding the Pathophysiology of Exosomes in Schistosomiasis: A New Direction for Disease Control and Prevention.

Schistosomiasis is a parasitic disease endemic to freshwater areas of Southeast Asia, Africa, and South America that is capable of causing serious damage to the internal organs. Recent studies have linked exosomes to the progression of schistosomiasis. These structures are important mediators for intercellular communication, assist cells to exchange proteins, lipids, and genetic material and have been shown to play critical roles during host–parasite interactions. This review aims to discuss the pathophysiology of exosomes in schistosomiasis and their roles in regulating the host immune response. Understanding how exosomes are involved in the pathogenesis of schistosomiasis may provide new perspectives in diagnosing and treating this neglected disease.

Praziquantel pharmacotherapy reduces systemic osteopontin levels and liver collagen content in murine schistosomiasis mansoni

The pathogenesis of schistosomiasis and the mechanism of disease regression after Praziquantel pharmacotherapy are not fully elucidated. Schistosoma mansoni egg antigens directly stimulate the expression of the profibrogenic molecule osteopontin (OPN), and systemic OPN levels strongly correlate with disease severity, suggesting its use as a potential morbidity biomarker. In this study, we investigated the impact of Praziquantel use on systemic OPN levels and on liver collagen deposition in chronic murine schistosomiasis. Praziquantel treatment significantly reduced systemic OPN levels and liver collagen deposition, indicating that OPN could be a reliable tool for monitoring PZQ efficacy and fibrosis regression in murine schistosomiasis.

Gas chromatography-mass spectrometry (GC/MS) reveals urine metabolites associated to light and heavy infections by Schistosoma mansoni in mice.

High-throughput profiling of metabolites has been used to identify metabolic changes in murine models as a response to the infection by the parasitic trematode Schistosoma. These investigations have contributed to our understanding on the pathogenesis of this tropical neglected disease, with a potential of helping diagnosis. Here, our study aimed to investigate the application of gas chromatography-mass spectrometry (GC/MS) on the profiling of urine metabolites from mice carrying infections by Schistosoma mansoni. Two larval infection doses created distinctive infection intensities in mice, whereby the heavily infected animals were found to release 25 times more eggs in faeces than lightly infected animals. Over 200 urine metabolites were identified from these animals by GC/MS, following two complementary derivatisation methods. A list of 14 individual metabolites with altered relative abundances between groups were identified. Most of the altered metabolites showed a trend of increased abundances in response to infection intensity, indicating host-specific metabolic alterations as a result of the disease. Hippurate, a metabolite which concentration is intimately modulated by the gut microbiota, was found to be highly correlated to infection intensity. Our study showed that urine metabolic profiling by GC/MS can distinguish non-infected animals from those carrying light and heavy infections by S. mansoni, revealing metabolites associated to the infection and providing insights on the pathogenesis of schistosomiasis.

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.

Therapeutic Potential of Human Umbilical Cord Blood Derived Mesenchymal Stem Cells in Murine Model of Hepatic Schistosomiasis

Background and Aim: The pathogenesis of schistosomiasis is mainly due to the host’s immune response against Schistosoma eggs trapped in tissues causing a granulomatous reaction. Recently, stem cell therapy has drawn much attention due to their potential for self-renewal and differentiation. The present study was designed to investigate the regenerative and antifibrotic potential of Human Umbilical Cord Blood derived Mesenchymal Stem Cells (HUCB-MSCs) in hepatic granuloma due to schistosomiasis mansoni in the experimental murine model. Material and Methods: Swiss Albino mice (n=70) were divided into 3 groups; Group A: 30 mice infected with S. mansoni cercariae and subjected to intrahepatic injection of HUCB-MSCs by a single dose of 1 million HUCB-MSCs at 12 weeks post infection (wpi), G (A1): 10 mice sacrificed at 16 (wpi), G (A2):10 mice sacrificed at 18 (wpi), G (A3): 10 mice sacrificed at 20 (wpi). Group B: 30 mice infected with S. mansoni cercariae (positive control), G (B1):10 mice sacrificed at 16 (wpi), G (B2):10 mice sacrificed at 18 (wpi), G (B3):10 mice sacrificed at 20 (wpi). Group C: 10 uninfected mice (negative control). Results: Treatment with HUCB-MSCs, showed an improvement in the histopathological picture of the liver with diminution in the size of granulomas and the overall fibrotic content. Hyperplasic changes in intrahepatic biliary radicals obviously decreased in test groups. Conclusion: The human umbilical cord blood-derived MSCs are promising and effective therapy for the treatment of diseased or damaged liver tissues.

Prior Toxoplasma Gondii Infection Ameliorates Liver Fibrosis Induced by Schistosoma Japonicum through Inhibiting Th2 Response and Improving Balance of Intestinal Flora in Mice.

Schistosomiasis is an immunopathogenic disease in which a T helper (Th) cell type 2-like response plays vital roles. Hepatic fibrosis is its main pathologic manifestations, which is the leading cause of hepatic cirrhosis. Co-infections of Schistosoma japonicum (Sj) with other pathogens are frequently encountered but are easily ignored in clinical studies, and effective therapeutic interventions are lacking. In this study, we explored the effect of Toxoplasma gondii (Tg) prior infection on Th1/Th2 response, community shifts in gut microbiome (GM), and the pathogenesis of schistosomiasis in murine hosts. Mice were prior infected with Tg before Sj infection. The effects of co-infection on Th1/Th2 response and hepatic fibrosis were analyzed. Furthermore, we investigated this issue by sequencing 16S rRNA from fecal specimens to define the GM profiles during co-infection. Tg prior infection markedly reduced the granuloma size and collagen deposit in livers against Sj infection. Prior infection promoted a shift toward Th1 immune response instead of Th2. Furthermore, Tg infection promoted the expansion of preponderant flora and Clostridiaceae was identified as a feature marker in the GM of the co-infection group. Redundancy analysis (RDA)/canonical correspondence analysis (CCA) results showed that liver fibrosis, Th1/Th2 cytokines were significantly correlated (P < 0.05) with the GM compositions. Tg infection inhibits hepatic fibrosis by downregulating Th2 immune response against Sj infection, and further promotes the GM shifts through “gut–liver axis” in the murine hosts. Our study may provide insights into potential anti-fibrosis strategies in co-infection individuals.

Inhibition of Rho-Kinase Downregulates Th17 Cells and Ameliorates Hepatic Fibrosis by Schistosoma japonicum Infection.

Background: Schistosomiasis is an immunopathogenic disease in which Th17 cells play vital roles. Hepatic granuloma formation and subsequent fibrosis are its main pathologic manifestations and the leading causes of hepatic cirrhosis, and effective therapeutic interventions are lacking. In this study, we explored the effects of fasudil, a selective RhoA–Rho-associated kinase (ROCK) inhibitor, on Th17 cells and the pathogenesis of schistosomiasis. Methods: Mice were infected with Schistosoma japonicum and treated with fasudil. The worm burden, hepatic granuloma formation, and fibrosis were evaluated. The roles of fasudil on Th17, Treg, and hepatic stellate cells were analyzed. Results: Fasudil therapy markedly reduced the granuloma size and collagen deposit in livers from mice infected with S. japonicum. However, fasudil therapy did not affect the worm burden in infected mice. The underlying cellular and molecular mechanisms were investigated. Fasudil suppressed the activation and induced the apoptosis of CD4+ T cells. Fasudil inhibited the differentiation and effector cytokine secretion of Th17 cells, whereas it upregulated Treg cells in vitro. It also restrained the in vivo interleukin (IL)-4 and IL-17 levels in infected mice. Fasudil directly induced the apoptosis of hepatic stellate cells and downregulated the expressions of hepatic fibrogenic genes, such as collagen type I (Col-I), Col-III, and transforming growth factor-1 (TGF-β1). These effects may contribute to its anti-pathogenic roles in schistosomiasis. Conclusions: Fasudil inhibits hepatic granuloma formation and fibrosis with downregulation of Th17 cells. Fasudil might serve as a novel therapeutic agent for hepatic fibrosis due to schistosome infections and perhaps other disorders.

The RIO protein kinase-encoding gene Sj-riok-2 is involved in key reproductive processes in Schistosoma japonicum

BackgroundSchistosomiasis is one of the most prevalent parasitic diseases worldwide and is caused by parasitic trematodes of the genus Schistosoma. The pathogenesis of schistosomiasis is caused by eggs whose production is the consequence of the pairing of schistosomes and the subsequent sexual maturation of the female. Previous studies have demonstrated that protein kinases are involved in processes leading to the male-induced differentiation of the female gonads, ovary and vitellarium. Right open reading frame protein kinase 2 (RIOK-2) is a member of the atypical kinase family and shown in other organisms to be responsible for ribosomal RNA biogenesis and cell-cycle progression, as well as involves in nematode development. However, nothing is known about its functions in any trematode including schistosome.MethodsWe isolated and characterized the riok-2 gene from S. japonicum, and detected the transcriptional profiles of Sj-riok-2 by using real-time PCR and in situ hybridization. RNAi-mediated knockdown of Sj-riok-2 was performed, mitotic activities were detected by EdU incorporation assay and morphological changes on organs were observed by confocal laser scanning microscope (CLSM).ResultsIn silico analyses of the amino acid sequence of Sj-RIOK-2 revealed typical features of this class of kinases including a winged helix (wHTH) domain and a RIO kinase domain. Sj-riok-2 is transcribed in different developmental stages of S. japonicum, with a higher abundance in adult females and eggs. Localization studies showed that Sj-riok-2 was mainly transcribed in female reproductive organs. Experiments with adult schistosomes in vitro demonstrated that the transcriptional level of Sj-riok-2 was affected by pairing. Knocking down Sj-riok-2 by RNAi reduced cell proliferation in the vitellarium and caused the increased amount of mature oocytes in ovary and an accumulation of eggs within the uterus.ConclusionsSj-riok-2 is involved in the reproductive development and maturation of female S. japonicum. Our findings provide first evidence for a pairing-dependent role of Sj-riok-2 in the reproductive development and maturation of female S. japonicum. Thus this study contributes to the understanding of molecular processes controlling reproduction in schistosomes.

Dynamics of Th9 cells and their potential role in immunopathogenesis of murine schistosomiasis

BackgroundTh1, Th2, Th17, Treg and Tfh cells play important roles in schistosomiasis. Th9 cells secrete IL-9 as a signature cytokine and contribute to several classes of inflammatory disease. However, the effects of Th9 cells in schistosomiasis are unknown. We aimed to explore the dynamic changes and potential roles of Th9 cells in the pathogenesis of hepatic egg granulomatous inflammation in mice infected with Schistosoma japonicum.MethodsTwenty mice with S. japonicum infection and five normal controls (NC) were used as models. The average areas of egg granulomas were estimated by hematoxylin-eosin (H & E) staining. Hepatic IL-9 and transcription factor PU.1 levels were detected by immunohistochemistry. Flow cytometry techniques were used to analyze the proportions of Th9 cells. With the help of ELISA, serum levels of IL-9 were examined.ResultsThe egg granulomas began to form from four weeks after infection and continued to develop. In parallel with the development of egg granulomas, the hepatic levels of IL-9 and PU.1 increased very slowly during the first four weeks post-infection and increased rapidly thereafter. Moreover, the proportions of splenic Th9 cells and levels of serum IL-9 had similar developmental trends with the egg granulomas.ConclusionThe proliferation of Th9 cells and levels of IL-9 were significantly higher in S. japonicum-infected mice compared to NC. In addition, dynamic changes of Th9 and IL-9 were synchronous with the developmental trend of hepatic egg granulomatous inflammation, suggesting that Th9 cells might be a new subset in the pathogenesis of schistosomiasis.

Enhanced inflammatory cell profiles in schistosomiasis-induced pulmonary vascular remodeling.

Schistosomiasis (bilharzia) is a neglected parasitic disease caused by trematode flatworms of the genus Schistosoma which affects over 240 million people worldwide. It is characterized by the formation of inflammatory granulomas around deposited parasite eggs. Recent studies have revealed that immune and inflammatory responses play a crucial role in pathogenesis of schistosomiasis. The aim of this paper is to systematically evaluate the number and distribution of inflammatory cells in S. mansoni-infected mice at different doses and time points. Immunohistochemistry was performed on lung and liver tissue sections from Schistosoma-infected mice and uninfected healthy controls. Positively stained cells in whole-lung/liver tissue sections, surrounding the eggs, and in the different compartments of the tissues, were counted. We found a significant increase in the number of mast cells (toluidine blue+), CD3+ cells, CD14+ cells, CD68+ cells, and CD15+ cells in Schistosoma-infected tissues compared with untreated healthy controls (P ≤ 0.05 for all). Our findings revealed altered and enhanced immune cell infiltration in schistosomiasis. We suggest that these cells may contribute to the pathophysiology of Schistosoma resulting in pulmonary vascular remodeling.

Molecular characterization of S. japonicum exosome-like vesicles reveals their regulatory roles in parasite-host interactions.

Secreted extracellular vesicles play an important role in pathogen-host interactions. Increased knowledge of schistosome extracellular vesicles could provide insights into schistosome-host interactions and enable the development of novel intervention strategies to inhibit parasitic processes and lessen disease transmission. Here, we describe biochemical characterization of Schistosoma japonicum exosome-like vesicles (S. japonicum EVs). A total of 403 proteins were identified in S. japonicum EVs, and bioinformatics analyses indicated that these proteins were mainly involved in binding, catalytic activity, and translation regulatory activity. Next, we characterized the population of small RNAs associated with S. japonicum EVs. Further studies demonstrated that mammalian cells could internalize S. japonicum EVs and transfer their cargo miRNAs to recipient cells. Additionally, we found that a specific miRNA, likely originating from a final host, ocu-miR-191–5p, is also associated with S. japonicum EVs. Overall, our findings demonstrate that S. japonicum EVs could be implicated in the pathogenesis of schistosomiasis via a mechanism involving the transfer of their cargo miRNAs to hosts. Our findings provide novel insights into the mechanisms of schistosome-host interactions.

Ocular pathological changes in hamsters experimentally infected with Schistosoma mansoni.

Ocular lesions have been reported in patients with schistosomiasis; however, the problem with studying schistosomal infection of the human eye is that biopsies are almost impossible to take, and histopathological examination of suspicious lesions can only be undertaken post-mortem or after enucleation. This work aimed to study the possible effects and pathogenesis of schistosomiasis on the eye. This study involved 55 hamsters; five hamsters remained non-infected and the remaining 50 hamsters were infected with Schistosoma mansoni cercariae. Infected hamsters were sacrificed on weeks 8, 12, 16 and 20 post-infection (pi). Eye sections were prepared and stained for histopathological and immunohistochemical studies. Histopathological changes detected in hamsters infected after 16 and 20 weeks included looseness and oedema of the innermost retinal layers together with hyperplastic polypoid growth. Neither eggs nor granulomata were detected in eye sections throughout the experimental period. Deposition of S. mansoni antigen was revealed in 35% of infected hamsters. Later, on weeks 16 and 20 pi, moderate subepithelial conjuctival deposits and marked subchoroidal and scleral deposition were detected. In conclusion, the deposition of schistosomal antigen and immune complexes may play a pivotal role in the ocular changes that occur in schistosomiasis, even in the absence of detectable Schistosoma eggs. Schistosomiasis should be suspected in cases with unexplained ophthalmological findings, especially in endemic areas.

Allograft inflammatory factor-1 alleviates liver disease of BALB/c mice infected with Schistosoma japonicum.

Allograft inflammatory factor-1 (AIF-1) plays an important role in various inflammatory conditions. Our previous study demonstrated that AIF-1 was over-expressed in the liver of BALB/c mice infected with Schistosoma japonicum and played significant role in the pathogenesis of schistosomiasis. The aim of this study was to focus on the effect of AIF-1 treatment on liver fibrosis and necrosis of BALB/c mice infected with S. japonicum. Seventy-two BALB/c mice were infected with cercariae of S. japonicum and then divided into three groups: AIF-1-treated group, saline-treated group, and control group. The vital signs, liver function, egg load, and hepatic pathological changes of the mice were assessed, and the levels of AIF-1 and TNF-α in the liver and spleen were measured at 5, 8, and 14 weeks postinfection. The treatment of AIF-1 on the mice infected with S. japonicum suppressed the expression of TNF-α and increased the effectiveness of AIF-1 in the liver and spleen at 14 weeks postinfection. Histopathological analysis and Masson trichrome staining for the liver tissues showed that the liver fibrosis and necrosis were alleviated previously compared with other infected mice at 14 weeks postinfection. The treatment of AIF-1 on the mice infected with S. japonicum can alleviate hepatic fibrosis and necrosis which indicate that AIF-1 use may prevent and cure the liver fibrosis.

CK2 Phosphorylation of Schistosoma mansoni HMGB1 Protein Regulates Its Cellular Traffic and Secretion but Not Its DNA Transactions

BackgroundThe 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.Principal FindingsWe 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.ConclusionsWe 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.

Evaluation of the role of angiogenic factors in the pathogenesis of schistosomiasis

Schistosomiasis is one disease produced by helminths, which affect many people in tropical areas. Granuloma formation is the main mechanism involved in the pathogenesis of this disease. Experimental studies have demonstrated angiogenesis (blood vessels formation from pre-existing vessels) in the initial phase of granuloma formation. In the present work, VEGF (vascular endothelial growth factor) levels were analyzed in sera from people diagnosed with different helminthic infections. Patients with schistosomiasis and filariasis had significantly high VEGF levels in compared with healthy people and patients diagnosed with hookworms. In addition, the effects of angiogenesis inhibition using anti-angiogenic factors (endostatin) were evaluated in a schistosomiasis murine model. A lesion decrease was observed in mice infected with Schistosoma mansoni and treated with endostatin. Finally, mechanisms of angiogenesis induction were studied and observed that cercariae antigens stimulated the angiogenic factors by host alveolar macrophages.

Identification and characterization of Schistosoma japonicum Sjp40, a potential antigen candidate for the early diagnosis of schistosomiasis

The pathogenesis of schistosomiasis is mainly caused by egg-induced granuloma formation and subsequent fibrosis. If Schistosoma japonicum infections could be detected in the early stage, especially before the egg deposition in the host tissues, the development of severe pathologic lesions might be prevented efficiently. The present study identified and characterized S. japonicum Sjp40, a potential antigen candidate for the early diagnosis of schistosomiasis. From the S. japonicum cercariae cDNA library, a clone encoding Sjp40 was identified by screening with the pooled rabbit sera collected on day 21 postinfection. Then, the recombinant Sjp40 protein (rSjp40) and monoclonal antibodies (McAbs) anti-rSjp40 were developed. The expression profiles of Sjp40 at 3 stages of S. japonicum, including egg, cercariae, and adult, were also determined at both mRNA and protein level, which displayed that the expression pattern of Sjp40 varied at different stages. Quantification of circulatory anti-Sjp40 IgG in the infected mice sera by time-resolved fluoroimmunoassay showed a statistically significant increase on days 21, 28, 35, and 42 postinfection compared with the mice sera prior to infection and the control mice. It was further confirmed by Western blot that all 8 clones of anti-rSjp40 McAbs could react specifically with the native antigen in S. japonicum cercariae, and rSjp40 could be recognized by the pooled infected mouse sera on days 21, 28, 35, and 42 postinfection as well as the pooled patient sera with acute schistosomiasis japonica. These findings indicated that Sjp40 and its antibodies are detectable from the host at a relatively early phase (day 21 postinfection with S. japonicum) and suggested that Sjp40 is a potential antigen candidate for the early diagnosis of schistosomiasis.

The extracellular release of Schistosoma mansoni HMGB1 nuclear protein is mediated by acetylation

Schistosoma mansoni HMGB1 (SmHMGB1) was revealed to be a substrate for the parasite histone acetyltransferases SmGCN5 and SmCBP1. We found that full-length SmHMGB1, as well as its HMG-box B (but not HMG-box A) were acetylated in vitro by SmGCN5 and SmCBP1. However, SmCBP1 was able to acetylate both substrates more efficiently than SmGCN5. Interestingly, the removal of the C-terminal acidic tail of SmHMGB1 (SmHMGB1ΔC) resulted in increased acetylation of the protein. We showed by mammalian cell transfection assays that SmHMGB1 and SmHMGB1ΔC were transported from the nucleus to the cytoplasm after sodium butyrate (NaB) treatment. Importantly, after NaB treatment, SmHMGB1 was also present outside the cell. Together, our data suggest that acetylation of SmHMGB1 plays a role in cellular trafficking, culminating with its secretion to the extracellular milieu. The possible role of SmHMGB1 acetylation in the pathogenesis of schistosomiasis is discussed.