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Schistosomiasis is a neglected zoonotic disease, and the liver fibrosis induced by Schistosoma japonicum infection poses a significant threat to human health. Traditionally, liver fibrosis in schistosomiasis has been attributed to eggs deposited in the liver, which trigger hepatic inflammation and fibrosis. However, our study reveals that schistosomula migration to the liver induces epithelial-to-mesenchymal transition (EMT) in liver sinusoidal endothelial cell (LSEC), thereby contributing to the progression of liver fibrosis. In the early stage of S. japonicum infection, mice exhibited a reduction in the proportion of LSEC and impairment of their function. RNA-sequencing revealed significant alterations in β-Klotho (KLB) expression in injured LSEC. Although KLB is known to exert anti-inflammatory functions as a co-receptor for fibroblast growth factor (FGF) in the liver, its role in LSEC EMT and schistosomiasis-induced liver fibrosis was unclear. Using SK-Hep1 cells, we found that KLB knockdown exacerbated EMT, whereas KLB over-expression attenuated EMT and decreased TGFβ1 secretion from LSEC, thereby suppressing LX-2 activation. In mice infected with S. japonicum , treatment with recombinant KLB protein or AAV8-KLB increased the LSEC population, mitigated EMT in both LSEC and liver tissues, ameliorated hepatic fibrosis, and inhibited TGFβ1 pathway activation. Our study reveals that KLB suppresses LSEC EMT induced by liver-stage schistosomula and TGFβ1 secretion, thereby inhibiting HSC activation and reducing liver fibrosis. Our findings highlight KLB as a promising therapeutic target for hepatic fibrosis in schistosomiasis.

Schistosomiasis is a tropical disease caused by trematode worms. The inflammatory response of the host to schistosome eggs leads to formation of granuloma in the liver and intestine. Praziquantel (PZQ) is still an effective treatment for schistosomiasis, however resistance development may reduce its efficacy. The current study investigated the possible immunomodulatory and anti-inflammatory action of rutin, a natural flavonoid compound isolated from garlic, on liver fibrotic markers in mice infected with S. mansoni in comparison to PZQ. Male albino CD1 mice were infected with 100 ± 2 S. mansoni cercariae/mouse and treated with garlic, rutin, or PZQ. At the end of the experiment, the liver and intestines were harvested for parasitological and histological assessment and to analyze the proinflammatory cytokine. Rutin significantly affects the pathological alterations caused by Schistosoma in the liver. This may be partially explained by a decrease in the number of eggs trapped in the tissues of the liver and a modification in the serum levels of certain cytokines, which are implicated in the formation of Schistosoma granuloma. In conclusion, rutin has strong anti-schistosome properties in vivo, raising the possibility that rutin might be further investigated as a therapy for S. mansoni.

Asian hepatointestinal schistosomiasis due to Schistosoma japonicum is prevalent in the Philippines and in Indonesia, while it is close to elimination in China. The second Asian schistosome, S. mekongi , is found in Cambodia and Laos. The main pathology caused by both species is liver fibrosis, which can cause significant morbidity and mortality, mainly due to portal hypertension leading to bleeding from esophageal varices. Ultrasonography was introduced several decades ago as a safe, fast, non-invasive, and relatively inexpensive technique for assessing chronic schistosomiasis-related hepatic pathology in the clinical and field settings. A standardized ultrasound protocol had been established by experts at a WHO-chaired meeting in Cairo, Egypt, in 1990. The peculiarities of sonomorphologic abnormalities caused by S. japonicum and S. mekongi were not sufficiently covered in the Cairo protocol and not addressed at all in the subsequent WHO chaired meeting in Niamey 1996. At a follow-up WHO-chaired meeting in Phnom Pehnh, Cambodia, in 2002, an attempt was made to develop a protocol for Asian schistosomiasis, but a protocol resulting from this meeting has never been published. Although several studies investigated the use of ultrasonography to assess S. japonicum - and S. mekongi -related sonomorphological morbidity across endemic areas the lack of a standardized protocol hampered the characterization of sonomorphologic abnormalities with regard to progression, reversibility, prognosis, and correlation to morbidity. In addition, the comparison of data from different endemic areas and populations remained difficult. Therefore, a WHO-chiared expert meeting took place in Basel, Switzerland in September 2024 with the aim to establish a standardized ultrasound protocol for reporting the pathology caused by S. japonicum and S. mekongi . The proposed protocol is described in this article. Graphical Abstract

Schistosomiasis (bilharzia) is a parasitic infection caused by trematodes of the Schistosoma genus and remains a significant health burden in endemic regions. Granulomatous host responses to deposited Schistosoma eggs in small veins and tissues result in progressive changes and characteristic imaging findings. This diagnostic radiological review synthesizes the published literature and highlights key and robust imaging findings that facilitate the diagnosis of Schistosoma mansoni and Schistosoma haematobium, with emphasis on modality-specific patterns and disease staging. Schistosoma mansoni primarily affects the liver, causing periportal fibrosis visible as “pipe-stem” echogenic thickening upon ultrasonography, which may progress to portal hypertension and chronic liver disease. Liver cirrhosis is the end-stage disease manifested as an irregular liver contour with surface nodularity and lobar redistribution as right lobe atrophy with left and/or caudate lobe hypertrophy. Schistosoma haematobium predominantly affects the genitourinary system, causing urinary bladder wall thickening and calcification. Early disease, within three months of infection, may present with fine calcification, firstly in the bladder base and then extending to the whole bladder and even to the ureters. Calcification appears as a line or two parallel lines on radiography and as a circle in axial computed tomography (CT) images, which is pathognomonic for early-stage Schistosomiasis. In contrast studies, including conventional urography and CT urography, Schistosoma eggs appear as bubble-like filling defects in the ureter, kidney, and bladder, manifested as ureteritis, pyelitis, and cystitis cystica. Late stages appear as coarse calcification, fibrosis, strictures, and reduced bladder capacity and are associated with an increased risk of bladder squamous cell carcinoma. Moreover, Schistosomiasis calcification can present in genital organs, especially in the seminal vesicles; in the prostate in males; and in the vulva, cervix, and perineum in females. Ultimately, Schistosoma mansoni and haematobium eggs can reach the spinal cord, leading to acute myelopathy with paraparesis, urinary retention, or paraplegia. Recognition of characteristic imaging patterns of Schistosomiasis is essential for early diagnosis, accurate staging, and prevention of long-term complications.

World Health Organization (WHO) guidelines for measuring global progress in schistosomiasis control classify individuals with Schistosoma spp. infections based on the concentration of excreted eggs. We assessed the associations between WHO infection intensity categories and morbidity prevalence for selected S. haematobium and S. mansoni morbidities in school-age children. A total of 22,488 children aged 6-15 years from monitoring and evaluation cohorts in Burkina Faso, Mali, Niger, Uganda, Tanzania, and Zambia from 2003-2008 were analyzed using Bayesian logistic regression. Models were utilized to evaluate associations between intensity categories and the prevalence of any urinary bladder lesion, any upper urinary tract lesion, microhematuria, and pain while urinating (for S. haematobium) and irregular hepatic ultrasound image pattern (C-F), enlarged portal vein, laboratory-confirmed diarrhea, and self-reported diarrhea (for S. mansoni) across participants with infection and morbidity data. S. haematobium infection intensity categories possessed consistent morbidity prevalence across surveys for multiple morbidities and participants with light infections had elevated morbidity levels, compared to negative participants. Conversely, S. mansoni infection intensity categories lacked association with prevalence of the morbidity measures assessed. Current status infection intensity categories for S. haematobium were associated with morbidity levels in school-age children, suggesting urogenital schistosomiasis morbidity can be predicted by an individual's intensity category. Conversely, S. mansoni infection intensity categories were not consistently indicative of childhood morbidity at baseline or during the first two years of a preventive chemotherapy control program.

The objectives of this study were to 1) evaluate the influence of treatment with praziquantel on the inflammatory milieu in maternal, placental, and cord blood, 2) assess the extent to which proinflammatory signatures in placental and cord blood impacts birth outcomes, and 3) evaluate the impact of other helminths on the inflammatory micro environment. This was a secondary analysis of samples from 369 mother-infant pairs participating in a randomized controlled trial of praziquantel given at 12-16 weeks' gestation. We performed regression analysis to address our study objectives. In maternal peripheral blood, the concentrations of CXCL8, and TNF receptor I and II decreased from 12 to 32 weeks' gestation, while IL-13 increased. Praziquantel treatment did not significantly alter the trajectory of the concentration of any of the cytokines examined. Hookworm infection was associated with elevated placental IL-1, CXCL8 and IFN-γ. The risk of small-for-gestational age increased with elevated IL-6, IL-10, and CXCL8 in cord blood. The risk of prematurity was increased when cord blood sTNFRI and placental IL-5 were elevated. Our study suggests that fetal cytokines, which may be related to infectious disease exposures, contribute to poor intrauterine growth. Additionally, hookworm infection influences cytokine concentrations at the maternal-fetal interface. ClinicalTrials.gov (NCT00486863).

Schistosoma haematobium infections are responsible for significant urinary tract (UT) complications. Schistosomiasis control programs aim to reduce morbidity, yet the extent of morbidity in preschool-aged children and the impact of treatment on morbidity reduction are not well studied. Our study was embedded in a randomized, placebo-controlled, single-blind trial in Côte d'Ivoire, which evaluated the efficacy and safety of three doses (20, 40 and 60 mg/kg) of praziquantel in school-aged (SAC) and preschool-aged (PSAC) children infected with S. haematobium. Enrolled children were invited to participate in an ultrasound examination prior and six months after treatment. At these time points 3 urine samples were collected for parasitological and clinical examinations. 162 PSAC and 141 SAC participated in the ultrasound examination at baseline, of which 128 PSAC and 122 SAC were present at follow-up. At baseline 43% (70/162) of PSAC had UT morbidity, mostly at bladder level and 7% had hydronephrosis. 67% (94/141) of SAC revealed mainly moderate UT pathology, 4% presented pseudopolyps on the bladder wall, and 6% had pyelectasis. At follow up, 45% of PSAC and 58% of SAC were S. haematobium positive, mostly harboring light infection intensities (41% and 51%, respectively). Microhematuria was present in 33% of PSAC and 42% of SAC and leukocyturia in 53% and 40% of PSAC and SAC, respectively. 50% (64/128) of PSAC and 58% (71/122) of SAC presented urinary tract morbidity, which was mainly mild. A significant correlation (p<0.05) was observed between praziquantel treatment and reversal of S. haematobium induced morbidity. Progression of UT pathology decreased with increasing praziquantel dosages. A worsening of morbidity was observed among children in the placebo group. Bladder morbidity is widespread among PSAC. Praziquantel treatment is significantly associated with the reversal of S. haematobium induced morbidity, which underscores the importance of preventive chemotherapy programs. These programs should be expanded to PSAC to prevent or decrease the prevalence of morbidity in young children. This trial is registered as an International Standard Randomized Controlled Trial, number ISRCTN15280205.

Background. Schistosome infections are often clinically silent, but some individuals develop severe pathological reactions. In several disease processes, T-helper 17 (Th17) cells have been linked to tissue injuries, while regulatory T cells (Tregs) are thought to downmodulate inflammatory reactions. We assessed whether bladder pathology in human Schistosoma haematobium infection is related to the balance of Th17 cells and Tregs. We used a murine model of Schistosoma mansoni infection to further investigate whether the peripheral profiles reflected ongoing events in tissues. Methods. We characterized T-helper cell subsets in the peripheral blood of children residing in a S. haematobium-endemic area and in the peripheral blood, spleen, and hepatic granulomas of S. mansoni–infected highpathology CBA mice and low-pathology C57BL/6 mice. Results. S. haematobium–infected children with bladder pathology had a significantly higher percentage of Th17 cells than those without pathology. Moreover, the Th17/Treg ratios were significantly higher in infected children with pathology, compared with infected children without pathology. Percentages of interleukin 17-producing cells were significantly higher in spleen and granulomas of CBA mice, compared with C57BL/6 mice. This difference was also reflected in the peripheral blood. Conclusions. This is the first study to indicate that Th17 cells may be involved in the pathogenesis of human schistosomiasis.

PurposeAlthough praziquantel (PZQ) has a wide use as an anti-schistosome agent, many of its imperfections and side effects have been reported in many studies. The current study aims to evaluate the curative effect of a natural dandelion extract (Taraxacum officinale) on schistosomiasis either alone or in combination with PZQ based on parasitological, immunological, histopathological and molecular investigations.MethodsMice were experimentally infected with Schistosoma mansoni cercariae and then divided into four groups, Schistosoma spp.-infected untreated group (IC group), Schistosoma spp.-infected group of mice treated with dandelion (I-Dn group), Schistosoma spp.-infected group of mice treated with PZQ (I-PZQ group), and Schistosoma spp.-infected group of mice treated with both PZQ and dandelion (I-PZQ + Dn group). Treatment started 45 days’ post-infection. Besides, non-infected, non-treated mice served as the negative healthy control group (HC group).ResultsThe present results indicated that dandelion administration significantly reduced the worm burden, ova number, and the number and diameter of hepatic granulomas as compared to the untreated infected group. The results also showed that the levels of IL-6 and TNF-α were significantly decreased in the combined treatment group (I-PZQ + Dn) as compared to the I-PZQ group. Administration of dandelion-only remarkably reduced AST and ALT activities associated with schistosomiasis. Moreover, hepatic DNA damage assessed by comet assay was significantly inhibited in the combined treated group compared to the infected untreated and PZQ treated groups.ConclusionThe results concluded that combined treatment of PZQ and dandelion extract improved immune response, decreased the number and diameter of granulomas, and inhibited DNA damage, indicating a reduction in liver fibrosis associated with schistosomiasis. The present study focused on the potential effect of dandelion as an adjunct medication for therapeutic properties of PZQ.

Background The main symptoms of schistosomiasis are granuloma and fibrosis, caused by Schistosoma eggs. Numerous types of cells and cytokines are involved in the progression of Schistosoma infection. As a class of innate immune cells, γδ T cells play critical roles in the early immune response. However, their role in modulating granuloma and fibrosis remains to be clarified. Methods Liver fibrosis in wild-type (WT) mice and T cell receptor (TCR) δ knockout (KO) mice infected with Schistosoma japonicum was examined via Masson’s trichrome staining of collagen deposition and quantitative reverse transcriptase-PCR (RT-PCR) of fibrosis-related genes. Granuloma was detected by hematoxylin-eosin (H&E) staining and quantified. Flow cytometry was used for immune cell profiling and for detecting cytokine secretion. The abundance of the related cytokines was measured using quantitative RT-PCR. Results The livers of S. japonicum -infected mice had significantly increased proportions of interleukin (IL)-17A producing γδ T cells and secreted IL-17A. Compared with the WT mice, TCR δ deficiency resulted in reduced pathological impairment and fibrosis in the liver and increased survival in infected mice. In addition, the profibrogenic effects of γδ T cells in infected mice were associated with enhanced CD11b + Gr-1 + cells, concurrent with increased expression of transforming growth factor (TGF)-β in the liver. Conclusions In this mouse model of Schistosoma infection, γδ T cells may promote liver fibrosis by recruiting CD11b + Gr-1 + cells. These findings shed new light on the pathogenesis of liver pathology in murine schistosomiasis.