Inhibition of hepatic natural killer cell function via the TIGIT receptor in schistosomiasis-induced liver fibrosis.

Schistosomiasis is a zoonotic parasitic disease. Schistosoma japonicum eggs deposited in the liver tissue induce egg granuloma formation and liver fibrosis, seriously threatening human health. Natural killer (NK) cells kill activated hepatic stellate cells (HSCs) or induce HSC apoptosis and inhibit the progression of liver fibrosis. However, the function of NK cells in liver fibrosis caused by S. japonicum infection is significantly inhibited. The mechanism of this inhibition remains unclear. Twenty mice were percutaneously infected with S. japonicum cercariae. Before infection and 2, 4, 6, and 8 weeks after infection, five mice were euthanized and dissected at each time point. Hepatic NK cells were isolated and transcriptome sequenced. The sequencing results showed that Tigit expression was high at 4-6 weeks post infection. This phenomenon was verified by reverse transcription quantitative PCR (RT-qPCR) and flow cytometry. NK cells derived from Tigit-/- and wild-type (WT) mice were co-cultured with HSCs. It was found that Tigit-/- NK cells induced apoptosis in a higher proportion of HSCs than WT NK cells. Schistosomiasis infection models of Tigit-/- and WT mice were established. The proportion and killing activity of hepatic NK cells were significantly higher in Tigit-/- mice than in WT mice. The degree of liver fibrosis in Tigit-/- mice was significantly lower than that in WT mice. NK cells were isolated from Tigit-/- and WT mice and injected via the tail vein into WT mice infected with S. japonicum. The degree of liver fibrosis in mice that received NK cell infusion reduced significantly, but there was no significant difference between mice that received NK cells from Tigit-/- and WT mice, respectively. Our findings indicate that Tigit knockout enhanced the function of NK cells and reduced the degree of liver fibrosis in schistosomiasis, thus providing a novel strategy for treating hepatic fibrosis induced by schistosomiasis.

Type 2 immunity: a two-edged sword in schistosomiasis immunopathology.

Schistosomiasis is the second most debilitating neglected tropical disease globally after malaria, with no available therapy to control disease-driven immunopathology. Although schistosomiasis induces a markedly heterogenous immune response, type 2 immunity is the dominating immune response following oviposition. While type 2 immunity has a crucial role in granuloma formation and host survival during the acute stage of disease, its chronic activation can result in tissue scarring, fibrosis, and organ impairment. Here, we discuss recent advances in schistosomiasis, demonstrating how different immune and non-immune cells and signaling pathways are involved in the induction, maintenance, and regulation of type 2 immunity. A better understanding of these immune responses during schistosomiasis is essential to inform the potential development of candidate therapeutic strategies that fine-tune type 2 immunity to ideally modulate schistosomiasis immunopathology.

A retrospective cross-sectional study: comparison of the clinicopathological features of schistosomal and non-schistosomal colorectal cancer in Central China.

AIM: To analyze the clinicopathological features of schistosomal and non-schistosomal colorectal cancer in Central China and compare them with other areas of the Yangtze River Basin. METHOD: The 501 cases of colorectal cancer (CRC) were retrospectively analyzed from 2020 to 2022. They were divided into two groups: 406 cases of colorectal cancer without schistosomiasis (CRC-NS) and 95 cases of colorectal cancer with schistosomiasis (CRC-S).The clinicopathological characteristics included the distribution of schistosomiasis eggs, patient age, sex, tumor differentiation, lymph node metastasis, and clinical stage. By retrieving the database, this study compared the clinicopathological differences of colorectal cancer with schistosomiasis in other areas of the Yangtze River basin. RESULTS: The cases of colorectal cancer with schistosomiasis accounted for 18.9%(95/501) in the study. The patients of CRC-S were older than the patients of CRC-NS (P = 0.002, P < 0.05). There was a statistical difference in the location of occurrence (P = 0.000, P < 0.05) between the two groups. There were no significant differences between CRC-S and CRC-NS in other clinicopathological features, such as sex (P = 0.054), Type(P = 0.242), histological type(P = 0.654), infiltrative depth(P = 0.811), differentiation(P = 0.837), lymph node metastasis(P = 0.574), intravascular tumor thrombus(P = 0.698), T stage(P = 0.354). In other areas of the Yangtze River Basin, there were statistical differences in the age of occurrence and T stage (P < 0.05) between colorectal cancer with schistosomiasis and non-schistosomal colorectal cancer. CONCLUSION: In Central China, colorectal cancer with chronic schistosomiasis infection occurs more in the rectum and sigmoid colon. It is more common in individuals over 60 years old, consistent with the findings in the Yangtze River Basin. Additionally, schistosomal colorectal cancer had a higher T stage in the Yangtze River Basin. This may be related to the malignant biological behavior of colorectal cancer and could result in a relatively poor prognosis. Therefore, the elderly population in schistosomiasis endemic areas should pay more attention to early screening and tumor prevention.

TREM2 expression promotes liver and peritoneal M2 macrophage polarization in mice infected with Schistosoma japonicum.

Schistosomiasis is a tropical parasitic disease that damages the liver and poses a serious threat to human health. Macrophages play a key role in the development of liver granulomas and fibrosis by undergoing polarization from M1 to M2 type during schistosomiasis. Therefore, regulating macrophage polarization is important for controlling pathological changes that occur during this disease. Triggering receptor expressed on myeloid cells 2 (TREM2) expressed on the surface of macrophages, dendritic cells and other immune cells has been shown to play a role in inhibiting inflammatory responses and regulating M2 macrophage polarization, however its role in macrophage polarization in schistosomiasis has not been investigated. In this study, we confirmed that TREM2 expression was upregulated in the livers and peritoneal macrophages of mice infected with Schistosoma japonicum. Moreover, the TREM2 expression trend correlated with the expression of M2 macrophage polarization-related molecules in the liver tissues of S. japonicum-infected mice. Using Trem2-/- mice, we also showed that Trem2 deletion inhibited Arg1 and Ym1 expression in liver tissues. Trem2 deletion also increased the number of F4/80 + CD86+ cells in peritoneal macrophages of infected mice. In summary, our study suggests that TREM2 may be involved in M2 macrophage polarization during schistosomiasis.

Diverging patterns of introgression from Schistosoma bovis across S. haematobium African lineages.

Hybridization is a fascinating evolutionary phenomenon that raises the question of how species maintain their integrity. Inter-species hybridization occurs between certain Schistosoma species that can cause important public health and veterinary issues. In particular hybrids between Schistosoma haematobium and S. bovis associated with humans and animals respectively are frequently identified in Africa. Recent genomic evidence indicates that some S. haematobium populations show signatures of genomic introgression from S. bovis. Here, we conducted a genomic comparative study and investigated the genomic relationships between S. haematobium, S. bovis and their hybrids using 19 isolates originating from a wide geographical range over Africa, including samples initially classified as S. haematobium (n = 11), S. bovis (n = 6) and S. haematobium x S. bovis hybrids (n = 2). Based on a whole genomic sequencing approach, we developed 56,181 SNPs that allowed a clear differentiation of S. bovis isolates from a genomic cluster including all S. haematobium isolates and a natural S. haematobium-bovis hybrid. All the isolates from the S. haematobium cluster except the isolate from Madagascar harbored signatures of genomic introgression from S. bovis. Isolates from Corsica, Mali and Egypt harbored the S. bovis-like Invadolysin gene, an introgressed tract that has been previously detected in some introgressed S. haematobium populations from Niger. Together our results highlight the fact that introgression from S. bovis is widespread across S. haematobium and that the observed introgression is unidirectional.

Repetitive schistosoma exposure causes perivascular lung fibrosis and persistent pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) can occur as a complication of schistosomiasis. In humans, schistosomiasis-PH persists despite antihelminthic therapy and parasite eradication. We hypothesized that persistent disease arises as a consequence of exposure repetition. METHODS: Following intraperitoneal sensitization, mice were experimentally exposed to Schistosoma eggs by intravenous injection, either once or three times repeatedly. The phenotype was characterized by right heart catheterization and tissue analysis. RESULTS: Following intraperitoneal sensitization, a single intravenous Schistosoma egg exposure resulted in a PH phenotype that peaked at 7-14 days, followed by spontaneous resolution. Three sequential exposures resulted in a persistent PH phenotype. Inflammatory cytokines were not significantly different between mice exposed to one or three egg doses, but there was an increase in perivascular fibrosis in those who received three egg doses. Significant perivascular fibrosis was also observed in autopsy specimens from patients who died of this condition. CONCLUSIONS: Repeatedly exposing mice to schistosomiasis causes a persistent PH phenotype, accompanied by perivascular fibrosis. Perivascular fibrosis may contribute to the persistent schistosomiasis-PH observed in humans with this disease.

The predictive value of CD4, CD8, and C-reactive protein in the prognosis of schistosomal and non-schistosomal colorectal cancer.

BACKGROUND: Although schistosomiasis has been basically eliminated, it has not been completely extinction in China and occasional outbreaks occur in Europe in recent years. The relationship between inflammation caused by Schistosoma japonicum and colorectal cancer (CRC) is still obscure, and the inflammation based prognostic systems of schistosomal colorectal (SCRC) has rarely been reported. AIM: To explore the different roles of tumor infiltrating lymphocytes (TILs) and C-reactive protein (CRP) in SCRC and in Non-schistosomal CRC (NSCRC), providing a possible predictive system to evaluate outcomes and to improve the risk stratification for CRC patients, especially for CRC patients with schistosomiasis. METHODS: Three hundred fifty-one CRC tumors were evaluated for density of CD4 + , CD8 + T cells and CRP in intratumoral and stromal compartments by immunohistochemical using tissue microarray. RESULTS: There were no association between TILs and CRP and schistosomiasis. Multivariate analysis identified stromal CD4 (sCD4) (p = 0.038), intratumoral CD8 (iCD8) (p = 0.003), schistosomiasis (p = 0.045) as independent prognostic factors for overall survival (OS) in the whole cohort; and sCD4 (p = 0.006) and iCD8 (p = 0.020) were independent prognostic factors for OS in the NSCRC and SCRC set, respectively. Besides, we found that there were no differences of TILs and CRP, which were distributed in different areas of tumor tissue, between CRC patients with and without schistosomiasis. CONCLUSION: The results remind us that different subtypes of TILs have distinguished biological behavior and prognosis value in the immune microenvironment of NSCRC and SCRC patients. Meanwhile, the findings require us to stratify patients with schistosomiasis and this might facilitate patient counseling and management.

Expression of microRNA-223 and microRNA-146b in serum and liver tissue of mice infected with Schistosoma mansoni.

MicroRNAs (miRNAs) play regulatory roles in several diseases. In schistosomiasis, the main pathological changes are caused by the granulomatous reaction induced by egg deposition. We aimed to study the changes in host miRNA-223 and miRNA-146b expression in relation to egg deposition and development of hepatic pathology in murine schistosomiasis mansoni. Blood and liver tissue samples were collected from non-infected mice (group I), S. mansoni-infected mice at the 4th, 8th, and 12th weeks post-infection (p.i.) (groups II-IV), and 4 weeks after praziquantel treatment (group V). The collected samples were processed for RNA extraction, reverse transcription, and real-time PCR analysis of miRNA-223 and miRNA-146b. miRNAs' relative expression was estimated by the ΔΔCt method. Liver tissue samples were examined for egg count estimation and histopathological evaluation. Results revealed that miRNA-223 was significantly downregulated in liver tissues 8 and 12 weeks p.i., whereas miRNA-146b expression increased gradually with the progression of infection with a significantly higher level at week 12 p.i. compared to week 4 p.i. Serum expression levels nearly followed the same pattern as the tissue levels. The dysregulated expression of miRNAs correlated with liver egg counts and was more obvious with the demonstration of chronic granulomas, fibrous transformation, and distorted hepatic architecture 12 weeks p.i. Restoration of normal expression levels was observed 4 weeks after treatment. Collectively, these findings provide new insights for in-depth understanding of host-parasite interaction in schistosomiasis and pave a new way for monitoring the progress of hepatic pathology before and after treatment.

Intestinal schistosomiasis masquerading as intestinal polyps.

BACKGROUND: Schistosomiasis is very common in the southern part of the Yangtze River Basin in China. It is mainly manifested as appendicitis, ulcers, hematomas, and thickening of the intestinal tract. Schistosomiasis of the appendix is rare, mainly manifested as appendicitis, which is easy to be misdiagnosed. CASE PRESENTATION: Here we report a rare case of a Chinese female whose intestinal mass manifested as intestinal polyps and was eventually diagnosed pathologically as schistosomiasis infection (appendix schistosomiasis). So far, there are rare relevant cases reported. CONCLUSIONS: Intestinal schistosomiasis is easily misdiagnosed, and appendix schistosomiasis is rare. The final diagnosis requires pathology, especially surgical pathology.

MicroRNA-351 promotes schistosomiasis-induced hepatic fibrosis by targeting the vitamin D receptor.

Aberrant expression of microRNAs (miRNAs) underlies a spectrum of human diseases including organ fibrosis, and hepatic stellate cells (HSCs) are the main effectors of hepatic fibrosis. Here, we showed that the expression of host miR-351 in HSCs was markedly reduced during the early stage of Schistosoma infection. However, this expression was significantly increased during the later stage of infection (after 52 d of infection). The elevated levels of miR-351 promoted hepatic fibrosis by targeting the vitamin D receptor (VDR), which is an antagonist of SMAD signaling. Importantly, efficient and sustained inhibition of miR-351 in liver tissues using the highly hepatotropic recombinant adeno-associated virus serotype 8 (rAAV8), alleviated the hepatic fibrosis, partially protecting the host from lethal schistosomiasis. In addition, we found that miR-351 is negatively regulated by IFN-γ in HSCs during infection. At the early stage of infection, the elevated levels of IFN-γ inhibited the expression of miR-351 in HSCs through activation of signal transducer and activator of transcription 1 and induction of IFN regulatory factor 2, which binds the promotor of pre-miR-351 Our study provides insights into the mechanisms by which miR-351 regulates schistosomiasis hepatic fibrosis and highlights the potential of rAAV8-mediated miR-351 inhibition as a therapeutic intervention for fibrotic diseases.

The Potential Role of Schistosome-Associated Factors as Therapeutic Modulators of the Immune System.

The parasites and eggs of helminths, including schistosomes, are associated with factors that can modulate the nature and outcomes of host immune responses, particularly enhancing type 2 immunity and impairing the effects of type 1 and type 17 immunity. The main species of schistosomes that cause infection in humans are capable of generating a microenvironment that allows survival of the parasite by evasion of the immune response. Schistosome infections are associated with beneficial effects on chronic immune disorders, including allergies, autoimmune diseases, and alloimmune responses. Recently, there has been increasing research interest in the role of schistosomes in immunoregulation during human infection, and the mechanisms underlying these roles continue to be investigated. Further studies may identify potential opportunities to develop new treatments for immune disease. In this review, we provide an update on the advances in our understanding of schistosome-associated modulation of the cells of the innate and adaptive immune systems as well as the potential role of schistosome-associated factors as therapeutic modulators of immune disorders, including allergies, autoimmune diseases, and transplant immunopathology. We also discuss potential opportunities for targeting schistosome-induced immunoregulation for future translation to the clinical setting.

Down-regulation of microRNA-203-3p initiates type 2 pathology during schistosome infection via elevation of interleukin-33.

The type 2 immune response is the central mechanism of disease progression in schistosomiasis, but the signals that induce it after infection remain elusive. Aberrant microRNA (miRNA) expression is a hallmark of human diseases including schistosomiasis, and targeting the deregulated miRNA can mitigate disease outcomes. Here, we demonstrate that efficient and sustained elevation of miR-203-3p in liver tissues, using the highly hepatotropic recombinant adeno-associated virus serotype 8 (rAAV8), protects mice against lethal schistosome infection by alleviating hepatic fibrosis. We show that miR-203-3p targets interleukin-33 (IL-33), an inducer of type 2 immunity, in hepatic stellate cells to regulate the expansion and IL-13 production of hepatic group 2 innate lymphoid cells during infection. Our study highlights the potential of rAAV8-mediated miR-203-3p elevation as a therapeutic intervention for fibrotic diseases.

Case Study: Schistosomiasis of the Endocervical Canal, A Rarely Reported Localization.

With a challenging diagnosis, schistosomiasis is a major public health issue worldwide, particularly in low-resource countries. The presence of Schistosoma ova in the female genital tract is a common finding, which may engender considerable suffering among women of child-bearing age. We report the asymptomatic case of endocervical schistosomiasis without visible exocervical lesions in a 41-yr-old Malagasy woman with human papillomavirus-positive status detected during a cervical cancer screening campaign in Andilampanahy, Madagascar. Schistosomiasis involving only the endocervical canal is rarely reported and can be diagnosed histologically with endocervical brushing, which therefore represents a minimally invasive and well-tolerated tool for disease detection.

An update on non-invasive urine diagnostics for human-infecting parasitic helminths: what more could be done and how?

Reliable diagnosis of human helminth infection(s) is essential for ongoing disease surveillance and disease elimination. Current WHO-recommended diagnostic assays are unreliable in low-endemic near-elimination settings and typically involve the invasive, onerous and potentially hazardous sampling of bodily fluids such as stool and blood, as well as tissue via biopsy. In contrast, diagnosis by use of non-invasive urine sampling is generally painless, more convenient and low risk. It negates the need for specialist staff, can usually be obtained immediately upon request and is better accepted by patients. In some instances, urine-based diagnostic assays have also been shown to provide a more reliable diagnosis of infection when compared to traditional methods that require alternative and more invasive bodily samples, particularly in low-endemicity settings. Given these relative benefits, we identify and review current research literature to evaluate whether non-invasive urine sampling is currently exploited to its full potential in the development of diagnostic tools for human helminthiases. Though further development, assessment and validation are needed before their routine use in control programmes, low-cost, rapid and reliable assays capable of detecting transrenal helminth-derived antigens and cell-free DNA show excellent promise for future use at the point-of-care in high-, medium- and even low-endemicity elimination settings.

Comparison of non-schistosomal colorectal cancer and schistosomal colorectal cancer.

AIM: The purpose of this study was to compare clinicopathological features of patients with non-schistosomal and schistosomal colorectal cancer to explore the effect of schistosomiasis on colorectal cancer (CRC) patients' clinical outcomes. METHODS: Three hundred fifty-one cases of CRC were retrospectively analyzed in this study. Survival curves were constructed by using the Kaplan-Meier (K-M) method. Univariate and multivariate Cox proportional hazard regression models were performed to identify associations with outcome variables. RESULTS: Colorectal cancer patients with schistosomiasis (CRC-S) were significantly older (P < 0.001) than the patients without schistosomiasis (CRC-NS). However, there were no significant differences between CRC-S and CRC-NS patients in other clinicopathological features. Schistosomiasis was associated with adverse overall survival (OS) upon K-M analysis (P = 0.0277). By univariate and multivariate analysis, gender (P = 0.003), TNM stage (P < 0.001), schistosomiasis (P = 0.025), lymphovascular invasion (P = 0.030), and lymph nodes positive for CRC (P < 0.001) were all independent predictors in the whole cohort. When patients were stratified according to clinical stage and lymph node metastasis state, schistosomiasis was also an independent predictor in patients with stage III-IV tumors and in patients with lymph node metastasis, but not in patients with stage I-II tumors and in patients without lymph node metastasis. CONCLUSION: Schistosomiasis was significantly correlated with OS, and it was an independent prognostic factor for OS in the whole cohort. When patients were stratified according to clinical stage and lymph node metastasis state, schistosomiasis was still an independently unfavorable prognosis factor for OS in patients with stage III-IV tumors or patients with lymph node metastasis.

Possible association and co-existence of schistosome infection and prostate cancer: A systematic review.

Male genital schistosomiasis (MGS) may result in eggs lodged in the prostate causing persistent inflammation that may play a major role in prostate carcinogenesis. Globally, prostate cancer (PCa) is one of the most common cancers and the global distribution of PCa overlaps with that of schistosomiasis infections, suggesting a probable causal relationship. Objectives of this review were to assess evidence of co-existence of schistosomiasis and PCa and possible causal association between the two diseases. Relevant literature published between 1950 and 2019 yielded 20 publications on schistosomiasis and PCa co-existence. Schistosoma (S.) haematobium and S. mansoni were associated with MGS manifestation and mostly prostate adenocarcinoma diagnosis. Effects of prostatic MGS infection progressed over time with high Schistosoma egg burden thought to contribute to the development of PCa. Causal association and mechanistic pathways of MGS on PCa development and the role of Schistosoma eggs on the development of PCa remains unestablished.

Inflammation-associated pathologies in a case of prostate schistosomiasis: Implications for a causal role in prostate carcinogenesis.

BACKGROUND: Urogenital infection with Schistosoma haematobium is a risk factor for the development of squamous cell carcinoma of the urinary bladder. The pathophysiology is thought to be mediated in part by inflammation, cellular damage, and bladder regeneration induced by the parasitic infection. Herein, we report an unusual case of schistosomiasis of the prostate that was found concurrent with prostate adenocarcinoma in a radical prostatectomy specimen from a man in the United States. METHODS: The infecting Schistosoma species was characterized via histomorphology and acid-fast stain. The concurrent Gleason score 6 prostate cancer was assessed for ETS transcription factor ERG (ERG), phosphatase and tensin homolog (PTEN), p27, and p53 status using immunohistochemistry (IHC). Cellular proliferation and the presence of intermediate cells in prostatic atrophy were assessed via immunostaining for Ki67 and CK903, respectively. RESULTS: Histomorphology and acid-fast stain of the infecting species were consistent with S. haematobium. We classified the Gleason score 6 prostate adenocarcinoma via IHC as ERG positive, PTEN intact, p27 intact, and without p53 nuclear accumulation. The prostatic epithelium immediately adjacent to the schistosomiasis-related granulomatous inflammation was atrophic and accompanied by increased cellular proliferation and the presence of intermediate cells. Upon literature review, we determined that prostate schistosomiasis is associated with a young age of prostate cancer diagnosis and highly aggressive prostate cancer. CONCLUSIONS: This is a rare case of prostate schistosomiasis in the United States; however, prostate schistosomiasis occurs frequently in endemic areas. The patient had traveled to a Schistosoma-endemic region, which was the likely location of exposure to the parasite. To our knowledge, this is the first report of the association of proliferative inflammatory atrophy and intermediate cells with schistosomiasis of the prostate. We propose that prostate schistosomiasis may be considered as a risk factor for the development of prostate cancer in geographic regions where Schistosoma species are endemic.

Schistosomiasis.

Schistosomiasis is a major cause of morbidity in the world; it is second only to malaria as a major infectious disease. Globally, it is estimated that the disease affects over 250 million people in 78 countries of the world and is responsible for some 280,000 deaths each year. The three major schistosomes infecting humans are Schistosoma mansoni, S. japonicum, and S. haematobium. This chapter covers a wide range of aspects of schistosomiasis, including basic biology of the parasites, epidemiology, immunopathology, treatment, control, vaccines, and genomics/proteomics. In this chapter, the reader will understand the significant toll this disease takes in terms of mortality and morbidity. A description of the various life stages of schistosomes is presented, which will be informative for both those unfamiliar with the disease and experienced scientists. Clinical and public health aspects are addressed that cover acute and chronic disease, diagnosis, current treatment regimens and alternative drugs, and schistosomiasis control programs. A brief overview of genomics and proteomics is included that details recent advances in the field that will help scientists investigate the molecular biology of schistosomes. The reader will take away an appreciation for general aspects of schistosomiasis and research advances.

Cannabinoid receptor-1 antagonism: a new perspective on treating a murine schistosomal liver fibrosis model.

BACKGROUND: Formation of schistosomal granulomata surrounding the ova can result in schistosomiasis-associated liver fibrosis (SSLF). The current standard of treatment is praziquantel (PZQ), which cannot effectively reverse SSLF. The role of the cannabinoid (CB) receptor family in liver fibrosis has recently been highlighted. OBJECTIVES: This study aimed to assess the therapeutic effect of CB1 receptor antagonism in reversing SSLF in a murine model of Schistosoma mansoni infection. METHODS: One hundred male Swiss albino mice were divided equally into five groups: healthy uninfected control (group I), infected control (group II), PZQ treated (group III), rimonabant (RIM) (SR141716, a CB1 receptor antagonist)-treated (group IV) and group V was treated with combined PZQ and RIM. Liver sections were obtained for histopathological examination, alpha-1 smooth muscle actin (α-SMA) immunostaining and assessment of CB1 receptor expression using real-time polymerase chain reaction (RT-PCR). FINDINGS: The most effective reduction in fibrotic marker levels and granuloma load was achieved by combined treatment with PZQ+RIM (group V): CB1 receptor expression (H = 26.612, p < 0.001), number of α-SMA-positive cells (F = 57.086, p < 0.001), % hepatic portal fibrosis (F = 42.849, p < 0.001) and number of granulomata (F = 69.088, p < 0.001). MAIN CONCLUSIONS: Combining PZQ with CB1 receptor antagonists yielded the best results in reversing SSLF. To our knowledge, this is the first study to test this regimen in S. mansoni infection.