Murine Model Of Schistosomiasis Research Articles

In vitro and in vivo efficacy of the amiodarone and praziquantel combination against the blood fluke Schistosoma mansoni.

Schistosomiasis, a widespread parasitic disease caused by the blood fluke of the genus Schistosoma, affects over 230 million people, primarily in developing countries. Praziquantel, the sole drug currently approved for schistosomiasis treatment, demonstrates effectiveness against patent infections. A recent study highlighted the antiparasitic properties of amiodarone, an anti-arrhythmic drug, exhibiting higher efficacy than praziquantel against prepatent infections. This study assessed the efficacy of amiodarone and praziquantel, both individually and in combination, against Schistosoma mansoni through comprehensive in vitro and in vivo experiments. In vitro experiments demonstrated synergistic activity (fractional inhibitory concentration index ≤0.5) for combinations of amiodarone with praziquantel. In a murine model of schistosomiasis featuring prepatent infections, treatments involving amiodarone (200 or 400 mg/kg) followed by praziquantel (200 or 400 mg/kg) yielded a substantial reduction in worm burden (60%-70%). Given the low efficacy of praziquantel in prepatent infections, combinations of amiodarone with praziquantel may offer clinical utility in the treatment of schistosomiasis.

P2Y2-P2X7 receptors cross-talk in primed mesenteric endothelial cells upregulates NF-κB signaling favoring mononuclear cell adhesion in schistosomiasis.

Schistosomiasis is an intravascular infectious disease that impacts over 200 million people globally. In its chronic stage, it leads to mesenteric inflammation with significant involvement of monocytes/macrophages. Endothelial cells lining the vessel lumens play a crucial role, and mount of evidence links this disease to a downregulation of endoprotective cell signaling favoring a primed and proinflammatory endothelial cell phenotype and therefore the loss of immunovascular homeostasis. One hallmark of infectious and inflammatory conditions is the release of nucleotides into the extracellular milieu, which, in turn, act as innate messengers, activating purinergic receptors and triggering cell-to-cell communication. ATP influences the progression of various diseases through P2X and P2Y purinergic receptor subtypes. Among these receptors, P2Y2 (P2Y2R) and P2X7 (P2X7R) receptors stand out, known for their roles in inflammation. However, their specific role in schistosomiasis has remained largely unexplored. Therefore, we hypothesized that endothelial P2Y2R and P2X7R could contribute to monocyte adhesion to mesenteric endothelial cells in schistosomiasis. Using a preclinical murine model of schistosomiasis associated with endothelial dysfunction and age-matched control mice, we showed that endothelial P2Y2R and P2X7R activation increased monocyte adhesion to cultured primary endothelial cells in both groups. However, a distinct upregulation of endothelial P2Y2R-driven canonical Ca2+ signaling was observed in the infected group, amplifying adhesion. In the control group, the coactivation of endothelial P2Y2R and P2X7R did not alter the maximal monocyte adhesion induced by each receptor individually. However, in the infected group, this coactivation induced a distinct upregulation of P2Y2R-P2X7R-driven canonical signaling, IL-1β release, and VCAM-1 expression, with underlying mechanisms involving inflammasome and NF-κB signaling. Therefore, current data suggest that schistosomiasis alters endothelial cell P2Y2R/P2X7R signaling during inflammation. These discoveries advance our understanding of schistosomiasis. This intricate interplay, driven by PAMP-triggered endothelial P2Y2R/P2X7R cross-talk, emerges as a potential key player in the mesenteric inflammation during schistosomiasis.

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

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

Antiparasitic Properties of Cardiovascular Agents against Human Intravascular Parasite Schistosoma mansoni.

The intravascular parasitic worm Schistosoma mansoni is a causative agent of schistosomiasis, a disease of great global public health significance. Praziquantel is the only drug available to treat schistosomiasis and there is an urgent demand for new anthelmintic agents. Adopting a phenotypic drug screening strategy, here, we evaluated the antiparasitic properties of 46 commercially available cardiovascular drugs against S. mansoni. From these screenings, we found that amiodarone, telmisartan, propafenone, methyldopa, and doxazosin affected the viability of schistosomes in vitro, with effective concentrations of 50% (EC50) and 90% (EC90) values ranging from 8 to 50 µM. These results were further supported by scanning electron microscopy analysis. Subsequently, the most effective drug (amiodarone) was further tested in a murine model of schistosomiasis for both early and chronic S. mansoni infections using a single oral dose of 400 mg/kg or 100 mg/kg daily for five consecutive days. Amiodarone had a low efficacy in chronic infection, with the worm and egg burden reduction ranging from 10 to 30%. In contrast, amiodarone caused a significant reduction in worm and egg burden in early infection (>50%). Comparatively, treatment with amiodarone is more effective in early infection than praziquantel, demonstrating the potential role of this cardiovascular drug as an antischistosomal agent.

Doxycycline aggravates granulomatous inflammation and lung microstructural remodeling induced by Schistosoma mansoni infection

Although doxycycline exhibits immunomodulatory properties, its effects on pulmonary infection by Schistosoma mansoni remain overlooked. Thus, we investigated the impact of this drug on lung granulomatous inflammation and microstructural remodeling in a murine model of schistosomiasis. Swiss mice were randomized in four groups: (i) uninfected, (ii) infected with S. mansoni and untreated, (iii) infected treated with praziquantel (Pzq; 200 mg/kg), and (iv) infected treated with Dox (50 mg/kg). Pz was administered in a single dose, and Dox for 60 days. S. mansoni induced marked granulomatous lung inflammation, which was associated to cytokines upregulation (IL-2, IL-4, IL-10, IFN-γ, TNF-α, and TGF-β), neutrophils and macrophages recruitment, alveolar collapse, lung fibrosis, and extensive depletion of elastic fibers. These parameters were attenuated by Pzq and aggravated by Dox. Exudative/productive granulomas were predominant in untreated and Dox-treated animals, while fibrotic granulomas were more frequent in Pzq-treated mice. The number and size of granulomas in Dox-treated animals was higher than untreated and Pzq-treated mice. Dox treatment inhibited the increase in MMP-1 and MMP-2 activity but upregulated myeloperoxidase and N-acetylglucosaminidase activity compared to untreated and Pzq-treated animals. Dox and Pzq exerted no effect on elastin depletion and upregulation of elastase activity. Together, our findings indicated that Dox aggravated granulomatous inflammation, accelerating lung microstructural remodeling by downregulating MMP-1 and MMP-2 activity without impair neutrophils and macrophages recruitment or elastase activity. Thus, Dox potentiates inflammatory damage associated with lung fibrosis, elastin depletion and massive alveolar collapse, profoundly subverting lung structure in S. mansoni-infected mice.

15β-Senecioyl-oxy-ent-kaur-16-en-19-oic Acid, a Diterpene Isolated from Baccharis lateralis, as Promising Oral Compound for the Treatment of Schistosomiasis.

Praziquantel is the only available drug to treat schistosomiasis, and therefore, urgent studies must be performed to identify new anthelmintic agents. This study reports the anthelmintic evaluation of two related ent-kaurane diterpenes isolated from aerial parts of Baccharis lateralis (Asteraceae), ent-kaur-16-en-19-oic acid (1) and 15β-senecioyl-oxy-ent-kaur-16-en-19-oic acid (2) against Schistosoma mansoni in vitro and in a murine model of schistosomiasis. Both compounds exhibited in vitro activity with lethal concentration 50% (LC50) values of 26.1 μM (1) and 11.6 μM (2) as well as reduced toxicity against human cell lines, revealing a good selectivity profile, mainly with compound 2 (selectivity index > 10). Compound 2 also decreased egg production and caused morphological alterations in the parasite reproductive system. In mice infected with S. mansoni, oral treatment with compound 2 at 400 mg/kg, the standard dose used in this model of schistosomiasis, caused a significant reduction in a total worm burden of 61.9% (P < 0.01). S. mansoni egg production, a key mechanism for both transmission and pathogenesis, was also markedly reduced. In addition, compound 2 achieved a significant reduction in hepatosplenomegaly. Therefore, the diterpene 15β-senecioyl-oxy-ent-kaur-16-en-19-oic acid (2) has an acceptable cytotoxicity profile and is orally active in a murine schistosomiasis model.

H1-antihistamines as antischistosomal drugs: in vitro and in vivo studies

BackgroundSchistosomiasis is a socioeconomically devastating parasitic infection afflicting hundreds of millions of people and animals worldwide. It is the most important helminth infection, and its treatment relies solely on the drug praziquantel. Oral H1-antihistamines are available worldwide, and these agents are among the most widely used of all medications in children and adults. Given the importance of the drug repositioning strategy, we evaluated the antischistosomal properties of the H1-antihistamine drugs commonly used in clinical practices.MethodsTwenty-one antihistamine drugs were initially screened against adult schistosomes ex vivo. Subsequently, we investigated the anthelmintic properties of these antihistamines in a murine model of schistosomiasis for both early and chronic S. mansoni infections at oral dosages of 400 mg/kg single dose or 100 mg/kg daily for five consecutive days. We also demonstrated and described the ability of three antihistamines to induce tegumental damage in schistosomes through the use of scanning electron microscopy.ResultsFrom phenotypic screening, we found that desloratadine, rupatadine, promethazine, and cinnarizine kill adult S. mansoni in vitro at low concentrations (5–15 µM). These results were further supported by scanning electron microscopy analysis. In an animal model, rupatadine and cinnarizine revealed moderate worm burden reductions in mice harboring either early or chronic S. mansoni infection. Egg production, a key mechanism for both transmission and pathogenesis, was also markedly inhibited by rupatadine and cinnarizine, and a significant reduction in hepatomegaly and splenomegaly was recorded. Although less effective, desloratadine also revealed significant activity against the adult and juvenile parasites.ConclusionsAlthough the worm burden reductions achieved are all only moderate, comparatively, treatment with any of the three antihistamines is more effective in early infection than praziquantel. On the other hand, the clinical use of H1-antihistamines for the treatment of schistosomiasis is highly unlikely.

Serum Exosomal miRNAs for Grading Hepatic Fibrosis Due to Schistosomiasis.

Chronic infection with Schistosoma japonicum or Schistosoma mansoni results in hepatic fibrosis of the human host. The staging of fibrosis is crucial for prognosis and to determine the need for treatment of patients with schistosomiasis. This study aimed to determine whether there is a correlation between the levels of serum exosomal micro-ribonucleic acids (miRNAs) (exomiRs) and fibrosis progression in schistosomiasis. Reference gene (RG) validation was initially carried out for the analysis of serum exomiRs expression in staging liver fibrosis caused by schistosome infection. The expression levels of liver fibrosis-associated exomiRs in serum were determined in a murine schistosomiasis model and in a cohort of Filipino schistosomiasis japonica patients (n = 104) with different liver fibrosis grades. Of twelve RG candidates validated, miR-103a-3p and miR-425-5p were determined to be the most stable genes in the murine schistosomiasis model and subjects from the schistosomiasis-endemic area, respectively. The temporal expression profiles of nine fibrosis-associated serum exomiRs, as well as their correlations with the liver pathologies, were determined in C57BL/6 mice during S. japonicum infection. The serum levels of three exomiRs (miR-92a-3p, miR-146a-5p and miR-532-5p) were able to distinguish subjects with fibrosis grades I-III from those with no fibrosis, but only the serum level of exosomal miR-146a-5p showed potential for distinguishing patients with mild (grades 0–I) versus severe fibrosis (grades II–III). The current data imply that serum exomiRs can be a supplementary tool for grading liver fibrosis in hepatosplenic schistosomiasis with moderate accuracy.

Promethazine exhibits antiparasitic properties in vitro and reduces worm burden, egg production, hepato-, and splenomegaly in a schistosomiasis animal model.

The treatment and control of schistosomiasis, a neglected disease that affects more than 200 million people worldwide, rely on the use of a single drug, praziquantel. A vaccine has yet to be developed and since new drug design and development is a lengthy and costly process, drug repurposing is a promising strategy. In this study, the efficacy of promethazine, a first-generation antihistamine, was evaluated against Schistosoma mansoni ex vivo and in a murine model of schistosomiasis. In vitro assays demonstrated that promethazine affected parasite motility, viability, and it induced severe tegumental damage in schistosomes. The LC50 of the drug was 5.84 μM. Similar to promethazine, schistosomes incubated with atropine, a classical anticholinergic drug, displayed reduced motor activity. In an animal model, promethazine treatment was introduced at an oral dose of 100 mg/kg for five successive days at different intervals from the time of infection, for the evaluation of the stage-specific susceptibility (pre-patent and patent infections). Various parasitological criteria indicated the in vivo antischistosomal effects of promethazine: there were significant reductions in worm burden, egg production, and hepato- and splenomegaly. The highest worm burden reduction was achieved with promethazine in patent infections (> 90%). Taken together, considering the importance of the repositioning of drugs in infectious diseases, especially those related to poverty, our data revealed the possibility of promethazine repositioning as an antischistosomal agent.

Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis.

BackgroundTreatment and control of schistosomiasis, one of the most insidious and serious parasitic diseases, depend almost entirely on a single drug, praziquantel. Since the funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, 73 nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in medical and veterinary fields were evaluated for their anti-schistosomal properties.MethodsThe efficacy of NSAIDs was first tested against adult Schistosoma mansoni ex vivo using phenotypic screening strategy, effective drugs were further tested in a murine model of schistosomiasis. The disease parameters measured were worm and egg burden, hepato- and splenomegaly.FindingsFrom 73 NSAIDs, five (mefenamic acid, tolfenamic acid, meclofenamic acid, celecoxib, and diclofenac) were identified to effectively kill schistosomes. These results were further supported by scanning electron microscopy analysis. In addition, the octanol-water partition coefficient, both for neutral and ionized species, revealed to be a critical property for the ex vivo activity profile. Compounds were then tested in vivo using both patent and a prepatent S. mansoni infection in a mouse model. The most effective NSAID was mefenamic acid, which highly reduced worm burden, egg production, and hepato- and splenomegaly.InterpretationThe treatment regimen used in this study is within the range for which mefenamic acid has been used in clinical practice, thus, it is demonstrated the capacity of mefenamic acid to act as a potent anti-schistosomal agent suitable for clinical repurposing in the treatment of schistosomiasis.

Correction to: In vitro schistosomicidal activity of tamoxifen and its effectiveness in a murine model of schistosomiasis at a single dose.

The original published version of this article contains error in Tables 1 and 2. Correct tables are presented here.

In vitro schistosomicidal activity of tamoxifen and its effectiveness in a murine model of schistosomiasis at a single dose.

Schistosomiasis is a neglected tropical disease affecting 220 million people worldwide. Praziquantel has proven to be effective against this parasitic disease, though there are increasing concerns regarding tolerance/resistance that calls for new drugs. Repurposing already existing and well-known drugs has been a desirable approach since it reduces time, costs, and ethical concerns. The anti-cancer drug tamoxifen (TAM) has been used worldwide for several decades to treat and prevent breast cancer. Previous reports stated that TAM affects Schistosoma hormonal physiology; however, no controlled schistosomicidal in vivo assays have been conducted. In this work, we evaluated the effect of TAM on female and male Schistosoma mansoni morphology, motility, and egg production. We further assessed worm survival and egg production in S. mansoni-infected mice. TAM induced morphological alterations in male and female parasites, as well as in eggs in vitro. Furthermore, in our in vivo experiments, one single dose of intraperitoneal TAM citrate reduced the total worm burden by 73% and led to a decrease in the amount of eggs in feces and low percentages of immature eggs in the small intestine wall. Eggs obtained from TAM citrate-treated mice were reduced in size and presented hyper-vacuolated structures. Our results suggest that TAM may be repurposed as a therapeutic alternative against S. mansoni infections.

Epiisopilosine alkaloid has activity against Schistosoma mansoni in mice without acute toxicity.

Schistosomiasis is a disease caused by parasites of the genus Schistosoma, currently affecting more than 200 million people. Among the various species of this parasite that infect humans, S. mansoni is the most common. Pharmacological treatment is limited to the use of a single drug, praziquantel (PZQ), despite reports of parasite resistance and low efficacy. It is therefore necessary to investigate new potential schistosomicidal compounds. In this study, we tested the efficacy of epiisopilosine (EPIIS) in a murine model of schistosomiasis. A single dose of EPIIS (100 or 400 mg/kg) administered orally to mice infected with adult S. mansoni resulted in reduced worm burden and egg production. The treatment with the lower dose of EPIIS (100 mg/kg) significantly reduced total worm burden by 60.61% (P < 0.001), as well as decreasing hepatosplenomegaly and egg excretion. Scanning electron microscopy revealed morphological changes in the worm tegument after treatment. Despite good activity of EPIIS in adult S. mansoni, oral treatment with single dose of EPIIS 100 mg/kg had only moderate effects in mice infected with juvenile S. mansoni. In addition, we performed cytotoxicity and toxicological studies with EPIIS and found no in vitro cytotoxicity (in HaCaT, and NIH-3T3 cells) at a concentration of 512 μg/mL. We also performed in silico analysis of toxicological properties and showed that EPIIS had low predicted toxicity. To confirm this, we investigated systemic acute toxicity in vivo by orally administering a 2000 mg/kg dose to Swiss mice. Treated mice showed no significant changes in hematological, biochemical, or histological parameters compared to non-treated animals. Epiisopilosine showed potential as a schistosomicidal drug: it did not cause acute toxicity and it displayed an acceptable safety profile in the animal model.

Inhibition of Notch Signaling Attenuates Schistosomiasis Hepatic Fibrosis via Blocking Macrophage M2 Polarization.

Macrophages play a key role in the pathogenesis of liver granuloma and fibrosis in schistosomiasis. However, the underlying mechanisms have not been fully characterized. This study revealed that the macrophages infiltrating the liver tissues in a murine model of Schistosoma japonica infection exhibited M2 functional polarization, and Notch1/Jagged1 signaling was significantly upregulated in the M2 polarized macrophages in vivo and in vitro. Furthermore, the blockade of Notch signaling pathway by a γ–secretase inhibitor could reverse macrophage M2 polarization in vitro and alleviate liver granuloma and fibrosis in the murine model of schistosomiasis. These results implied that the Notch1/Jagged1 signaling-dependent M2 polarization of macrophages might play an important role in liver granuloma and fibrosis in schistosomiasis, and the inhibition of Notch1/Jagged1 signaling might provide a novel therapeutic approach to administrate patients with schistosomiasis.

In Vivo MRI Assessment of Hepatic and Splenic Disease in a Murine Model of Schistosomiasis [corrected

BackgroundSchistosomiasis (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 FindingsCBA/J mice were imaged at 11.75T 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/SignificanceOur 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.

Inconsistent Protective Efficacy and Marked Polymorphism Limits the Value of Schistosoma japonicum Tetraspanin-2 as a Vaccine Target

Background Schistosoma mansoni tetraspanin 2 (Sm-TSP-2) has been shown to be strongly recognized by IgG1 and IgG3 antibodies from individuals putatively resistant to schistosome infection, but not chronically infected people, and to induce high levels of protection against challenge infection in the murine model of schistosomiasis. Amplification by PCR of homologous sequences from male and female S. japonicum worms showed the presence of 7 different clusters or subclasses of S. japonicum TSP-2. We determined the protective efficacy of one subclass – Sj-TSP-2e.Methodology/Principal FindingsFollowing the alignment of 211 cDNAs, we identified 7 clusters encoding S. japonicum TSP-2 (Sj-TSP-2) based on sequence variation in the large extracellular loop (LEL) region with differing frequency of transcription in male and female worms. Quantitative PCR analysis revealed elevated expression of Sj-TSP-2 in adult worms compared with other life cycle stages. We expressed in E. coli the LEL region of one of the clusters which exhibited a high frequency of transcription in female worms, and showed the purified recombinant protein (Sj-TSP-2e) was recognised by 43.1% of sera obtained from confirmed schistosomiasis japonica patients. Vaccination of mice with the recombinant protein induced high levels of IgG1 and IgG2 antibodies, but no consistent protective efficacy against challenge infection was elicited in three independent trials.Conclusions/SignificanceThe highly polymorphic nature of the Sj-TSP-2 gene at the transcriptional level may limit the value of Sj-TSP-2 as a target for future S. japonicum vaccine development.

Granulomatous-like immune reaction and hepatic fibrosis induced by Schistosoma haematobium immature worms

Golden hamsters were inoculated with Schistosoma haematobium cercariae to examine histological lesions at different time points over an 18 month period of infection. Hamsters were sacrificed 26 weeks and 82 weeks after inoculation. The parasite was found in the blood and in the liver of infected animals as was expected, but we found exclusively male worms, no female worms nor eggs. Interestingly we observed unexpected hepatic lesions induced by S. haematobium adult male worms alone in the golden hamster, characteristic of schistosome eggs. Samples from liver, kidneys, lungs, bladder and gastrointestinal tract were collected during necropsy to evaluate injuries induced by S. haematobium. Notably we observed hepatitis in the liver of infected hamsters, no lesions were found in other organs. We also found liver fibrosis in infected hamsters. This study provides further experimental evidence for the role that schistosome worms, and their derived antigens, may play in the pathology of the infection and modulation of liver chronic inflammation in the murine model of schistosomiasis.

Interference with hemozoin formation represents an important mechanism of schistosomicidal action of antimalarial quinoline methanols.

BackgroundThe parasitic trematode Schistosoma mansoni is one of the major causative agents of human schistosomiasis, which afflicts 200 million people worldwide. Praziquantel remains the main drug used for schistosomiasis treatment, and reliance on the single therapy has been prompting the search for new therapeutic compounds against this disease. Our group has demonstrated that heme crystallization into hemozoin (Hz) within the S. mansoni gut is a major heme detoxification route with lipid droplets involved in this process and acting as a potential chemotherapeutical target. In the present work, we investigated the effects of three antimalarial compounds, quinine (QN), quinidine (QND) and quinacrine (QCR) in a murine schistosomiasis model by using a combination of biochemical, cell biology and molecular biology approaches.Methodology/Principal FindingsTreatment of S. mansoni-infected female Swiss mice with daily intraperitoneal injections of QN, and QND (75 mg/kg/day) from the 11th to 17th day after infection caused significant decreases in worm burden (39%–61%) and egg production (42%–98%). Hz formation was significantly inhibited (40%–65%) in female worms recovered from QN- and QND-treated mice and correlated with reduction in the female worm burden. We also observed that QN treatment promoted remarkable ultrastructural changes in male and female worms, particularly in the gut epithelium and reduced the granulomatous reaction to parasite eggs trapped in the liver. Microarray gene expression analysis indicated that QN treatment increased the expression of transcripts related to musculature, protein synthesis and repair mechanisms.ConclusionsThe overall significant reduction in several disease burden parameters by the antimalarial quinoline methanols indicates that interference with Hz formation in S. mansoni represents an important mechanism of schistosomicidal action of these compounds and points out the heme crystallization process as a valid chemotherapeutic target to treat schistosomiasis.

Opposing roles for IL‐13 and IL‐13 receptor α2 in health and disease

Interleukin (IL)-13 is a key inducer of several type-2 cytokine-dependent pathologies. It regulates inflammation, mucus production, tissue remodeling, and fibrosis. Consequently, it has become an important therapeutic target for a number of debilitating illnesses, including asthma, idiopathic pulmonary fibrosis, ulcerative colitis, as well as several other diseases in which IL-13 is believed to be overproduced. In the murine model of schistosomiasis, IL-13 has emerged as a central mediator of chronic infection-induced liver pathology. Although IL-4, IL-5, IL-10, and IL-13 each regulate distinct aspects of the granulomatous inflammatory response, IL-13 was identified as the primary mediator of liver fibrosis. Thus, elucidating the mechanisms that regulate the production and function of IL-13 has become an intensive area of research. IL-13 signaling is mediated by the type-2 IL-4 receptor, which consists of the IL-4R alpha and IL-13R alpha 1 chains. However, another IL-13-binding chain, IL-13R alpha 2, appears to strongly inhibit the activity of IL-13. Animals deficient in IL-13R alpha 2 fail to downmodulate granuloma formation in the chronic phase of infection. They also develop severe IL-13-dependent fibrosis and portal hypertension and quickly succumb to the infection. Here, we summarize findings from the schistosomiasis model, which illustrate opposing activities for IL-13 and IL-13R alpha 2 in health and disease.

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