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Background: ARFI elastrography has been used as a noninvasive method to assess the severity of liver fibrosis in viral hepatitis, although with few studies in schistosomiasis mansoni. We aimed to evaluate the performance of point shear wave elastography (pSWE) for predicting significant periportal fibrosis (PPF) in schistosomotic patients and to determine its best cutoff point., Methodology/principal Findings: This cross-sectional study included 358 adult schistosomotic patients subjected to US and pSWE on the right lobe. Two hundred two patients (62.0%) were women, with a median age of 54 (ranging 18-92) years. The pSWE measurements were compared to the US patterns of PPF, as gold standard, according to the Niamey classification. The performance of pSWE was calculated as the area under the ROC curve (AUC). Patients were further classified into two groups: 86 patients with mild PPF and 272 patients with significant PPF. The median pSWE of the significant fibrosis group was higher (1.40 m/s) than that of mild fibrosis group (1.14 m/s, p<0.001). AUC was 0.719 with ≤1.11 m/s as the best cutoff value for excluding significant PPF. Sensitivity and negative predictive values were 80.5% and 40.5%, respectively. Whereas, for confirming significant PPF, the best cutoff value was >1.39 m/s, with specificity of 86.1% and positive predictive value of 92.0%., Conclusions/significance: pSWE was able to differentiate significant from mild PPF, with better performance to predict significant PPF., Competing Interests: The authors have declared that no competing interests exist.

MicroRNAs (miRNAs) are short, non-coding RNAs that repress the translation of target gene transcripts. They have been implicated in various activities such as cell proliferation, survival, differentiation, migration and metabolism. We report here the first known miRNome and transcriptome analysis of human livers displaying advanced fibrosis due to Schistosoma japonicum infection. We present evidence that hsa-miR-150-5p, hsa-miR-10a-5p, hsa-miR-199a-3p, hsa-miR-4521, hsa-miR-222/221, hsa-miR-663b and hsa-miR-143-3p (associated without correction) play an important role in hepatic fibrosis by acting on metabolism, organization of the extracellular matrix proteins, lipid mobilization and limitation of oxidative damage stress., (Copyright © 2017 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.)

Schistosoma eggs cause chronic liver inflammation and a complex disease characterized by hepatic fibrosis (HF) and splenomegaly (SplM). FOXP3+ Tregs could regulate inflammation, but it is unclear where these cells are produced and what roles they play in human schistosomiasis. We investigated blood and spleen FOXP3+ Tregs in Chinese fishermen with lifelong exposure to Schistosoma japonicum and various degrees of liver and spleen disease. FOXP3+ Tregs accounted for 4.3% of CD4+ T cells and 41.2% of FOXP3+CD4+ T cells; they could be divided into CD45RA-FOXP3hi effector (eTregs) and CD45RA+FOXP3low naive Tregs. Blood Treg levels were high in severe HF (+1.3; p = 0.004) and in SplM (+1.03, p = 0.03). Multivariate regression showed that severe HF (+0.85, p = 0.01) and SplM (+0.97; p = 0.05) were independently associated with the higher proportion of Tregs in the blood. This effect was mostly due to an increase in the proportion of eTregs in the blood of HF+++ (+0.9%; p = 0.04) and SplM (+0.9%; p = 0.04) patients. The proportion of eTregs expressing CXCR3 in the blood was lower in the HF+++ patients (37.4 +/- 5.9%) than in those with milder fibrosis (51.7 ± 2%; p = 0.009), whereas proportion were similar for cells expressing CD25hi, CCR7, and CTLA-4. Splenectomy improves symptoms and was associated with decreases in blood FOXP3+ Treg (-2.5; p<0.001) and eTreg (-1.3; p = 0.03) levels. SplM spleens contained a high proportion of eTregs with CXCR3, CCR5 and CTLA4 upregulation and CCR7 downregulation. This, and the strong expression of ligands of CXCR3 and CCR5 in the liver (n = 8) but not in the spleen suggested that spleen eTregs migrated to Th1-infiltrated liver tissues. Such migration may be attenuated in hepatosplenic patients due to lower levels of CXCR3 expression on Tregs (p = 0.009). Thus, higher blood Treg levels are associated with severe liver disease and splenomegaly. Our data are consistent with the hypothesis that the spleen is a major source of Tregs in subjects with splenomegaly. In most cases, Tregs migrate to the Th1-infiltrated liver and the lower levels of CXCR3+ Tregs in the blood of patients with severe schistosomiasis suggest that decreases in Treg migration sites of inflammation may aggravate the disease.

Background: Schistosomiasis (or bilharzia), a major parasitic disease, affects more than 260 million people worldwide. In chronic cases of intestinal schistosomiasis caused by trematodes of the Schistosoma genus, hepatic fibrosis develops as a host immune response to the helminth eggs, followed by potentially lethal portal hypertension. In this study, we characterized hepatic and splenic features of a murine model of intestinal schistosomiasis using in vivo magnetic resonance imaging (MRI) and evaluated the transverse relaxation time T2 as a non-invasive imaging biomarker for monitoring hepatic fibrogenesis., Methodology/principal Findings: CBA/J mice were imaged at 11.75 T two, six and ten weeks after percutaneous infection with Schistosoma mansoni. In vivo imaging studies were completed with histology at the last two time points. Anatomical MRI allowed detection of typical manifestations of the intestinal disease such as significant hepato- and splenomegaly, and dilation of the portal vein as early as six weeks, with further aggravation at 10 weeks after infection. Liver multifocal lesions observed by MRI in infected animals at 10 weeks post infection corresponded to granulomatous inflammation and intergranulomatous fibrosis with METAVIR scores up to A2F2. While most healthy hepatic tissue showed T2 values below 14 ms, these lesions were characterized by a T2 greater than 16 ms. The area fraction of increased T2 correlated (rS = 0.83) with the area fraction of Sirius Red stained collagen in histological sections. A continuous liver T2* decrease was also measured while brown pigments in macrophages were detected at histology. These findings suggest accumulation of hematin in infected livers., Conclusions/significance: Our multiparametric MRI approach confirms that this murine model replicates hepatic and splenic manifestations of human intestinal schistosomiasis. Quantitative T2 mapping proved sensitive to assess liver fibrogenesis non-invasively and may therefore constitute an objective imaging biomarker for treatment monitoring in diseases involving hepatic fibrosis.

Unlabelled: Interleukin (IL)-22 acts on epithelia, hepatocytes, and pancreatic cells and stimulates innate immunity, tissue protection, and repair. IL-22 may also cause inflammation and abnormal cell proliferation. The binding of IL-22 to its receptor is competed by IL-22 binding protein (IL-22BP), which may limit the deleterious effects of IL-22. The role of IL-22 and IL-22BP in chronic liver diseases is unknown. We addressed this question in individuals chronically infected with schistosomes or hepatitis C virus (HCV). We first demonstrate that schistosome eggs stimulate production of IL-22 transcripts and inhibit accumulation of IL22-BP transcripts in schistosome-infected mice, and that schistosome eggs selectively stimulate production of IL-22 in cultures of blood leukocytes from individuals chronically infected with Schistosoma japonicum. High IL-22 levels in cultures correlated with protection against hepatic fibrosis and portal hypertension. To test further the implication of IL-22/IL-22BP in hepatic disease, we analyzed common genetic variants of IL22RA2, which encodes IL-22BP, and found that the genotypes, AA, GG of rs6570136 (P = 0.003; odds ratio [OR] = 2), and CC, TT of rs2064501 (P = 0.01; OR = 2), were associated with severe fibrosis in Chinese infected with S. japonicum. We confirmed this result in Sudanese (rs6570136 GG [P = 0.0007; OR = 8.2], rs2064501 TT [P = 0.02; OR = 3.1]), and Brazilians (rs6570136 GG [P = 0.003; OR = 26], rs2064501 TC, TT (P = 0.03; OR = 11]) infected with S. mansoni. The aggravating genotypes were associated with high IL22RA2 transcripts levels. Furthermore, these same variants were also associated with HCV-induced fibrosis and cirrhosis (rs6570136 GG, GA [P = 0.007; OR = 1.7], rs2064501 TT, TC (P = 0.004; OR = 2.4])., Conclusions: These results provide strong evidence that IL-22 protects against and IL-22BP aggravates liver fibrosis and cirrhosis in humans with chronic liver infections. Thus, pharmacological modulation of IL-22 BP may be an effective strategy to limit cirrhosis., (© 2014 by the American Association for the Study of Liver Diseases.)

An association study of a cohort of 177 Sudanese patients infected with Schistosoma mansoni [82 (46%) males and 95 (54%) females] was conducted to evaluate the factors controlling the regression of liver fibrosis 39 months after treatment with praziquantel using ultrasound evaluation. Periportal fibrosis (PPF) was regressed in 63 (35.6%) patients, while the disease progressed to higher grades in 24 (13.6%) patients. The grade of PPF did not change in 90 (50.8%) patients. The mean values of portal vein diameter, splenic vein diameter and index liver size in subjects in whom PPF regressed after treatment were significantly lower than in subjects in whom the disease was progressed (P<0.0001, P=0.031 and P=0.003, respectively). The progression of hepatic fibrosis in males (15, 8.5%) was greater than that in females (9, 5.1%). Patients with regression or progression phenotypes tend to cluster in certain families. Our study indicated that regression, progression and stabilization of PPF after praziquantel therapy is controlled by gender, age, grade of fibrosis and possibly inherited factors.

Abnormal fibrosis occurs during chronic hepatic inflammations and is the principal cause of death in hepatitis C virus and schistosome infections. Hepatic fibrosis (HF) may develop either slowly or rapidly in schistosome-infected subjects. This depends, in part, on a major genetic control exerted by genes of chromosome 6q23. A gene (connective tissue growth factor [CTGF]) is located in that region that encodes a strongly fibrogenic molecule. We show that the single nucleotide polymorphism (SNP) rs9402373 that lies close to CTGF is associated with severe HF (P = 2 x 10(-6); odds ratio [OR] = 2.01; confidence interval of OR [CI] = 1.51-2.7) in two Chinese samples, in Sudanese, and in Brazilians infected with either Schistosoma japonicum or S. mansoni. Furthermore, SNP rs12526196, also located close to CTGF, is independently associated with severe fibrosis (P = 6 x 10(-4); OR = 1.94; CI = 1.32-2.82) in the Chinese and Sudanese subjects. Both variants affect nuclear factor binding and may alter gene transcription or transcript stability. The identified variants may be valuable markers for the prediction of disease progression, and identify a critical step in the development of HF that could be a target for chemotherapy.

Background: Schistosoma japonicum is the most pathogenic agent of hepatosplenic schistosomiasis. It causes fibrosis of the central (CentF) and peripheral (PerF) portal areas. We investigated whether CentF and PerF in Chinese fishermen infected with S. japonicum were associated with an abnormal production of cytokines and chemokines that, in experimental models, have been implicated in the regulation of fibrosis., Methods: Cytokines were measured by enzyme-linked immunosorbent assay in cultures of peripheral blood mononuclear cells from 127 patients, after stimulation with S. japonicum egg antigens. Data were analyzed by logistic regression that included age, sex, number of treatment episodes, alcohol use, and exposure as covariates., Results: CentF was associated with low levels of interleukin (IL)-10 (P= .0004), regulated on activation normally T cell expressed and secreted (P= .0004), and macrophage inflammatory protein-1alpha (P= .007). In a multivariate analysis, only IL-10 was associated with CentF (odds ratio [OR], 10.8; 95% confidence interval [CI], 3.2-38; P= .0004). Splenomegaly was also associated with low IL-10 production and, independently, with CentF. In multivariate analysis, PerF was associated with low production of interferon (IFN)-gamma (OR, 8.2; 95% CI, 2-33; P= .0035) but not with production of IL-10., Conclusions: IL-10 is associated with protection against central fibrosis, because of its anti-inflammatory and antifibrosis effects. IFN-gamma is associated with protection against PerF, which depends more on egg load and egg-associated toxicity.

Schistosome infection is a major public health concern affecting millions of people living in tropical regions of Africa, Asia, and South America. Schistosomes cause mild clinical symptoms in most subjects, whereas a small proportion of individuals presents severe clinical disease (as periportal fibrosis (PPF)) that may lead to death. Severe PPF results from an abnormal deposition of extracellular matrix proteins in the periportal spaces due to a chronic inflammation triggered by eggs and schistosome Ags. Extracellular matrix protein production is regulated by a number of cytokines, including IFN-gamma. We have now screened putative polymorphic sites within this gene in a population living in an endemic area for Schistosoma mansoni. Two polymorphisms located in the third intron of the IFN-gamma gene are associated with PPF. The IFN-gamma +2109 A/G polymorphism is associated with a higher risk for developing PPF, whereas the IFN-gamma +3810 G/A polymorphism is associated with less PPF. The polymorphisms result in changes in nuclear protein interactions with the intronic regions of the gene, suggesting that they may modify IFN-gamma mRNA expression. These results are consistent with the results of previous studies. Indeed, PPF is controlled by a major locus located on chromosome 6q22-q23, closely linked to the gene encoding the alpha-chain of the IFN-gamma receptor, and low IFN-gamma producers have been shown to have an increased risk of severe PPF. Together, these observations support the view that IFN-gamma expression and subsequent signal transduction play a critical role in the control of PPF in human hepatic schistosome infection (S. mansoni).

Hepatic periportal fibrosis, which affects 5-10% of subjects infected by Schistosoma mansoni, is caused by the T cell-dependent granuloma that develop around schistosome eggs. Experimental models of infection have shown that granuloma and fibrosis are tightly regulated by cytokines. However, it is unknown why advanced periportal fibrosis occurs only in certain subjects. The goal of the present study was to evaluate the cytokine response of S. mansoni-infected subjects with advanced liver disease in an attempt to relate susceptibility to periportal fibrosis with an abnormal production of cytokines that regulate granuloma and fibrosis. Fibrosis was evaluated by ultrasound on 795 inhabitants of a Sudanese village in which S. mansoni is endemic: advanced periportal fibrosis was observed in 12% of the population; 35% of the affected subjects exhibited signs of portal hypertension. Age (odds ratio (OR), 11.5), gender (OR, 4.2), and infection levels (OR, 2.2) were significantly (p < or = 0.01) associated with hepatic fibrosis. Cytokines produced by egg-stimulated blood mononuclear cells from 99 subjects were measured (75 with no or mild fibrosis; 24 subjects with advanced fibrosis). Multivariate analysis of cytokine levels showed that high IFN-gamma levels were associated with a marked reduction of the risk of fibrosis (p = 0.01; OR, 0.1); in contrast, high TNF-alpha levels were associated with an increased risk (p = 0.05; OR, 4.6) of periportal fibrosis. Moreover, infection levels were negatively associated with IFN-gamma production. These results with observations in experimental models strongly suggest that IFN-gamma plays a key role in the protection of S. mansoni-infected patients against periportal fibrosis, whereas TNF-alpha may aggravate the disease.