Schistosomiasis-associated pulmonary hypertension unveils disrupted murine gut-lung microbiome and reduced endoprotective Caveolin-1/BMPR2 expression.

Schistosomiasis-associated Pulmonary Arterial Hypertension (Sch-PAH) is a life-threatening complication of chronic S. mansoni infection that can lead to heart failure and death. During PAH, the expansion of apoptosis-resistant endothelial cells (ECs) has been extensively reported; however, therapeutic approaches to prevent the progression or reversal of this pathological phenotype remain clinically challenging. Previously, we showed that depletion of the anti-apoptotic protein Caveolin-1 (Cav-1) by shedding extracellular vesicles contributes to shifting endoprotective bone morphogenetic protein receptor 2 (BMPR2) towards transforming growth factor beta (TGF-ß)-mediated survival of an abnormal EC phenotype. However, the mechanism underlying the reduced endoprotection in PAH remains unclear. Interestingly, recent findings indicate that, similar to the gut, healthy human lungs are populated by diverse microbiota, and their composition depends significantly on intrinsic and extrinsic host factors, including infection. Despite the current knowledge that the disruption of the gut microbiome contributes to the development of PAH, the role of the lung microbiome remains unclear. Thus, using a preclinical animal model of Sch-PAH, we tested whether S. mansoni infection alters the gut-lung microbiome composition and causes EC injury, initiating the expansion of an abnormal EC phenotype observed in PAH. Indeed, in vivo stimulation with S. mansoni eggs significantly altered the gut-lung microbiome profile, in addition to promoting injury to the lung vasculature, characterized by increased apoptotic markers and loss of endoprotective expression of lung Cav-1 and BMPR2. Moreover, S. mansoni egg stimulus induced severe pulmonary vascular remodeling, leading to elevated right ventricular systolic pressure and hypertrophy, characteristic of PAH. In vitro, exposure to the immunodominant S. mansoni egg antigen p40 activated TLR4/CD14-mediated transient phosphorylation of Cav-1 at Tyr14 in human lung microvascular EC (HMVEC-L), culminating in a mild reduction of Cav-1 expression, but failed to promote death and shedding of extracellular vesicles observed in vivo. Altogether, these data suggest that disruption of the host-associated gut-lung microbiota may be essential for the emergence and expansion of the abnormal lung endothelial phenotype observed in PAH, in addition to S. mansoni eggs and antigens.

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.

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.

Immunohistochemical expression of CD117/KIT, HER2, and Erß in schistosomal and non-schistosomal urothelial carcinoma of Egyptian patients.

Bladder carcinoma is an endemic problem in Egypt with schistosomiasis being an additional risk factor. Due to gender disparities, Erß investigation and its role in modulating chemosensitivity are studied. CD117/KIT expression is also considered since the emergence of the targets of the tyrosine kinase inhibitor imatinib mesylate (Gleevec). HER2 is one of the established therapeutic targets in many cancers. We aimed to investigate CD117/KIT immunoexpression in schistosomal and non-schistosomal urothelial carcinoma of Egyptian patients and its relationship with HER2 and Erß expressions, correlating it with pertinent variables that will help to provide better treatment options of possible combined targeted and hormonal therapy that might be effective against this aggressive malignancy. Sixty cases of bladder carcinoma were tested. Depending on the schistosomiasis association status of each case, two groups have been established with 30 cases each. CD117/KIT, HER2, and ERß immunostaining were done and correlated with clinico- immuno-pathological parameters. CD117/KIT expression was seen in 71.7% of cases that correlated significantly with schistosomiasis (P = 0.01). In addition, a positive correlation was detected between schistosomiasis association and the percentage of immunostained cells and intensity score of CD117/KIT with P = 0.027, 0.01, respectively. 30% and 61.7% of cases were positively stained with HER2 and Erß, respectively, with no significant relation with schistosomiasis. Due to the high expression, we found further clinical trials are needed to offer individualized targeted therapeutic options in urothelial tumors using anti-CD117/KIT, HER2, and ERß other than limited traditional chemo- and nontargeted therapies.

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-1ß 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.

Schistosoma mansoni infection decreases IL-33-mRNA expression and increases CXCL9 and CXCL10 production by peripheral blood cells.

Schistosoma mansoni infections, particularly egg antigens, induce Th2-dominant granulomatous responses accompanied by remarkable immunoregulatory mechanisms that avoid intense fibrosis. Interleukin (IL)-33 is a cytokine that stimulates the early activation of Th2 responses, and its soluble ST2 receptor (sST2) avoids granulomatous response, as well as CXCL9 and CXCL10 chemokines that have antifibrotic activity. However, in schistosomiasis, these molecules have not been suitably studied. Therefore, this study aimed to measure IL-33 and sST2 RNA, cytokines, and chemokines in peripheral blood cultures from individuals living in schistosomiasis-endemic areas. Peripheral blood cells from individuals with S. mansoni (n = 34) and non-infected individuals (n = 31) were cultured under mitogen stimulation. Supernatant chemokines and cytokines were evaluated using a cytometric bead array, and IL-33 and sST2 mRNA expression was measured using qPCR. Infected individuals showed higher levels of CXCL8, CXCL9, CXCL10, IFN-γ, TNF-α, IL-6, IL-2, IL-4, and IL-10; there was a lower expression of IL-33 mRNA and similar expression of sST2mRNA in infected than non-infected individuals. In conclusion, for the first time, we demonstrated lower IL-33mRNA expression and high levels of the antifibrotic chemokines CXCL9 and CXCL10 in schistosomiasis mansoni, which could control exacerbations of the disease in individuals from endemic areas.

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.

MicroRNA 200a inhibits liver fibrosis of schistosoma.

MicroRNA 200a (miR-200a) can inhibit the activation and proliferation of hepatic stellate cells (HSCs) through the transforming growth factor-ß (TGF-ß) signaling pathway, and improve fibrotic lesions. However, to date, there is no study exploring the role of miR-200a in schistosomiasis liver fibrosis (SLF). In this study, 64 healthy female Balb/c mice were selected and randomly divided into four groups: normal control group (non-infected schistosomiasis group), schistosomiasis model group, Lenti-NC group (lentivirus-negative control group), and Lenti-miR-200a group (lentivirus experimental group). Fluorescence quantitative PCR detection was used to measure the expression level of RNA. HE and Masson staining were used to observe the pathological changes of mouse liver tissue. Furthermore, ELISA was used to detect the serum concentrations of inflammation factors. We found that the expression level of miR-200a in liver tissues gradually decreased with the development of SLF. However, fibrosis factors (α-SMA and TGF-ß2) and inflammatory cytokines (IL-4 and IFN-γ) in liver tissues and serum increased and the expression level of Colla I reached its peak in the 6th week of infection. Besides, compared with the schistosomiasis group and Lenti-NC group, the Lenti-NC group had lower levels of α-SMA, TGF-ß2 and Colla I (P > 0.05). Furthermore, inflammatory cells and blue collagen fibers appeared and they increased with the development of infection in the schistosomiasis group and Lenti-NC group, but these changes reduced significantly in Lenti-miR-200a group. Our study demonstrated that upregulation of miR-200a might contribute to inhibiting schistosomiasis liver fibrosis.

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

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

Immunological and Biochemical Interplay between Cytokines, Oxidative Stress and Schistosomiasis.

The host-parasite schistosome relationship relies heavily on the interplay between the strategies imposed by the schistosome worm and the defense mechanisms the host uses to counter the line of attack of the parasite. The ultimate goal of the schistosome parasite entails five important steps: evade elimination tactics, survive within the human host, develop into adult forms, propagate in large numbers, and transmit from one host to the next. The aim of the parasitized host on the other hand is either to cure or limit infection. Therefore, it is a battle between two conflicting aspirations. From the host's standpoint, infection accompanies a plethora of immunological consequences; some are set in place to defend the host, while most end up promoting chronic disease, which ultimately crosses paths with oxidative stress and cancer. Understanding these networks provides attractive opportunities for anti-schistosome therapeutic development. Hence, this review discusses the mechanisms by which schistosomes modulate the human immune response with ultimate links to oxidative stress and genetic instability.

Synthesis and Antibody Binding Studies of Schistosome-Derived Oligo-α-(1-2)-l-Fucosides.

Schistosomiasis is caused by blood-dwelling parasitic trematodes of the genus Schistosoma and is classified by the WHO as the second most socioeconomically devastating parasitic disease, second only to malaria. Schistosoma expresses a complex array of glycans as part of glycoproteins and glycolipids that can be targeted by both the adaptive and the innate part of the immune system. Some of these glycans can be used for diagnostic purposes. A subgroup of schistosome glycans is decorated with unique α-(1-2)-fucosides and it has been shown that these often multi-fucosylated fragments are prime targets for antibodies generated during infection. Since these α-(1-2)-fucosides cannot be obtained in sufficient purity from biological sources, we set out to develop an effective route of synthesis towards α-(1-2)-oligofucosides of varying length. Here we describe the exploration of two different approaches, starting from either end of the fucose chains. The oligosaccharides have been attached to gold nanoparticles and used in an enzyme-linked immunosorbent assay ELISA and a microarray format to probe antibody binding. We show that binding to the oligofucosides of antibodies in sera of infected people depends on the length of the oligofucose chains, with the largest glycans showing most binding.

Characterization of class II fumarase from Schistosoma mansoni provides the molecular basis for selective inhibition.

Schistosomiasis is a neglected tropical disease that affects more than 250 million people worldwide. The only drug available for its treatment undergoes first-pass hepatic metabolism and is not capable of preventing reinfection, which makes the search of new therapies urgently needed. Due to the essential role of fumarases in metabolism, these enzymes represent potential targets for developing novel schistosomiasis treatments. Here, we evaluate the expression profiles for class I and class II fumarases from Schistosoma mansoni (SmFHI and SmFHII, respectively), and report the complete characterization of SmFHII. The first SmFHII structure in complex with L-malate was determined at 1.85 Å resolution. The significant thermoshift observed for SmFHII in the presence of identified ligands makes the differential scanning fluorimetry an adequate technique for ligand screening. A complete kinetic characterization of SmFHII was performed, and comparison with the human fumarase (HsFH) revealed differences regarding the turnover number (kcat). Structural characterization allowed us to identify differences between SmFHII and HsFH that could be explored to design new selective inhibitors. This work represents the very first step towards validate the fumarases as drug targets to treat schistosomiasis. Our results provide the structural basis to rational search for selective ligands.

Arachidonic Acid Is a Safe and Efficacious Schistosomicide, and an Endoschistosomicide in Natural and Experimental Infections, and Cysteine Peptidase Vaccinated Hosts.

Blood flukes of the genus Schistosoma are covered by a protective heptalaminated, double lipid bilayer surface membrane. Large amounts of sphingomyelin (SM) in the outer leaflet form with surrounding water molecules a tight hydrogen bond barrier, which allows entry of nutrients and prevents access of host immune effectors. Excessive hydrolysis of SM to phosphoryl choline and ceramide via activation of the parasite tegument-associated neutral sphingomyelinase (nSMase) with the polyunsaturated fatty acid, arachidonic acid (ARA) leads to parasite death, via allowing exposure of apical membrane antigens to antibody-dependent cell-mediated cytotoxicity (ADCC), and accumulation of the pro-apoptotic ceramide. Surface membrane nSMase represents, thus, a worm Achilles heel, and ARA a valid schistosomicide. Several experiments conducted in vitro using larval, juvenile, and adult Schistosoma mansoni and Schistosoma haematobium documented ARA schistosomicidal potential. Arachidonic acid schistosomicidal action was shown to be safe and efficacious in mice and hamsters infected with S. mansoni and S. haematobium, respectively, and in children with light S. mansoni infection. A combination of praziquantel and ARA led to outstanding cure rates in children with heavy S. mansoni infection. Additionally, ample evidence was obtained for the powerful ARA ovocidal potential in vivo and in vitro against S. mansoni and S. haematobium liver and intestine eggs. Studies documented ARA as an endogenous schistosomicide in the final mammalian and intermediate snail hosts, and in mice and hamsters, immunized with the cysteine peptidase-based vaccine. These findings together support our advocating the nutrient ARA as the safe and efficacious schistosomicide of the future.

Schistosoma antigens as activators of inflammasome pathway: from an unexpected stimulus to an intriguing role.

Parasites of the genus Schistosoma are organisms capable of living for decades within the definitive host. They interfere with the immune response by interacting with host's receptors. In this review, we discuss from the first reports to the most recent discoveries regarding the ability of Schistosoma antigens in triggering intracellular receptors and inducing inflammasome activation.

Upregulation of KSRP by miR-27b attenuates schistosomiasis-induced hepatic fibrosis by targeting TGF-ß1.

Hepatic stellate cells (HSCs) are the main effectors for various types of hepatic fibrosis, including Schistosome-induced hepatic fibrosis. Multiple inflammatory cytokines/chemokines, such as transforming growth factor-ß1 (TGF-ß1), activate HSCs, and contribute to the development of hepatic fibrosis. MicroRNAs regulate gene expression at the posttranscriptional level and are involved in regulation of inflammatory cytokine/chemokine synthesis. In this study, we showed that soluble egg antigen (SEA) stimulation and Schistosoma japonicum infection downregulate miR-27b expression and increase KH-type splicing regulatory protein (KSRP) mRNA and protein levels in vitro and in vivo. miR-27b regulates the stabilization of TGF-ß1 mRNA through targeting KSRP by interacting with their AU-rich elements in hepatocytes and non-parenchymal cells, which has an effect on the activation of HSCs. Importantly, our results have shown that either knockdown miR-27b or overexpression of KSRP attenuates S. japonicum-induced hepatic fibrosis in vivo. Therefore, our study highlights the crucial role of miR-27b and KSRP in the negative regulation of immune reactions in hepatocyte and non-parenchymal cells in response to SEA stimulation and S. japonicum infection. It reveals that manipulation of miR-27b or KSRP might be a useful strategy not only for treating Schistosome-induced hepatic fibrosis but also for curing hepatic fibrosis in general.

Proteomic analysis of adult Schistosoma mekongi somatic and excretory-secretory proteins.

Schistosoma mekongi is a causative agent of human schistosomiasis. There is limited knowledge of the molecular biology of S. mekongi and very few studies have examined drug targets, vaccine candidates and diagnostic biomarkers for S. mekongi. To explore the biology of S. mekongi, computational as well as experimental approaches were performed on S. mekongi males and females to identify excretory-secretory (ES) proteins and proteins that are differentially expressed between genders. According to bioinformatic prediction, the S. mekongi ES product was approximately 4.7% of total annotated transcriptome sequences. The classical secretory pathway was the main process to secrete proteins. Mass spectrometry-based quantification of male and female adult S. mekongi proteins was performed. We identified 174 and 156 differential expression of proteins in male and female worms, respectively. The dominant male-biased proteins were involved in actin filament-based processes, microtubule-based processes, biosynthetic processes and homeostatic processes. The major female-biased proteins were related to biosynthetic processes, organelle organization and signal transduction. An experimental approach identified 88 proteins in the S. mekongi secretome. The S. mekongi ES proteins mainly contributed to nutrient uptake, essential substance supply and host immune evasion. This research identifies proteins in the S. mekongi secretome and provides information on ES proteins that are differentially expressed between S. mekongi genders. These findings will contribute to S. mekongi drug and vaccine development. In addition, the study enhances our understanding of basic S. mekongi biology.

Structure-Based Design, Synthesis, and Biological Evaluation of Triazole-Based smHDAC8 Inhibitors.

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial screening revealed the triazole-based hydroxamate 2 b (N-hydroxy-1-phenyl-1H-1,2,3-triazole-4-carboxamide) exhibiting potent inhibitory activity toward the novel antiparasitic target Schistosoma mansoni histone deacetylase 8 (smHDAC8) and promising selectivity over the major human HDACs. Subsequent crystallographic studies of the 2 b/smHDAC8 complex revealed key interactions between the inhibitor and the enzyme's active site, thus explaining the unique selectivity profile of the inhibitor. Further chemical modifications of 2 b led to the discovery of 4-fluorophenoxy derivative 21 (1-[5-chloro-2-(4-fluorophenoxy)phenyl]-N-hydroxy-1H-1,2,3-triazole-4-carboxamide), a nanomolar smHDAC8 inhibitor (IC50 =0.5 µM), exceeding the smHDAC8 inhibitory activity of 2 b and SAHA (vorinostat), while exhibiting an improved selectivity profile over the investigated human HDACs. Collectively, this study reveals specific interactions between smHDAC8 and the synthesized triazole-based inhibitors and demonstrates that these small molecules represent promising lead structures, which could be further developed in the search for novel drugs for the treatment of schistosomiasis.

Metabolic Programming of Macrophages: Implications in the Pathogenesis of Granulomatous Disease.

Metabolic reprogramming is rapidly gaining appreciation in the etiology of immune cell dysfunction in a variety of diseases. Tuberculosis, schistosomiasis, and sarcoidosis represent an important class of diseases characterized by the formation of granulomas, where macrophages are causatively implicated in disease pathogenesis. Recent studies support the incidence of macrophage metabolic reprogramming in granulomas of both infectious and non-infectious origin. These publications identify the mechanistic target of rapamycin (mTOR), as well as the major regulators of lipid metabolism and cellular energy balance, peroxisome proliferator receptor gamma (PPAR-γ) and adenosine monophosphate-activated protein kinase (AMPK), respectively, as key players in the pathological progression of granulomas. In this review, we present a comprehensive breakdown of emerging research on the link between macrophage cell metabolism and granulomas of different etiology, and how parallels can be drawn between different forms of granulomatous disease. In particular, we discuss the role of PPAR-γ signaling and lipid metabolism, which are currently the best-represented metabolic pathways in this context, and we highlight dysregulated lipid metabolism as a common denominator in granulomatous disease progression. This review therefore aims to highlight metabolic mechanisms of granuloma immune cell fate and open up research questions for the identification of potential therapeutic targets in the future.

Discovery of novel Schistosoma mansoni PDE4A inhibitors as potential agents against schistosomiasis.

Aim: Due to the urgent need for effective drugs to treat schistosomiasis that act through a known molecular mechanism of action, we focused on a target-based approach with the aim to discover inhibitors of a cyclic nucleotide phosphodiesterase from Schistosoma mansoni (SmPDE4A). Materials & methods: To discover new inhibitors of SmPDE4A homology models of the enzyme structure were constructed based on known human and protozoan homologs. The best two models were selected for subsequent virtual screening of our in-house chemical library. Results & conclusion: A total of 25 library compounds were selected for experimental confirmation as SmPDE4A inhibitors and after dose-response experiments, three top hits were identified. The results presented validate the virtual screening approach to identify new inhibitors for clinically relevant phosphodiesterases.

The C-type Lectin Receptor-Driven, Th17 Cell-Mediated Severe Pathology in Schistosomiasis: Not All Immune Responses to Helminth Parasites Are Th2 Dominated.

Schistosomiasis is a major helminthic disease in which damage to the affected organs is orchestrated by a pathogenic host CD4 T helper (Th) cell-mediated immune response against parasite eggs. In the case of the species Schistosoma mansoni, the resulting granulomatous inflammation and fibrosis takes place in the liver and intestines. The magnitude of disease varies greatly from individual to individual but in a minority of patients, there is severe disease and death. S. mansoni infection in a murine model similarly results in marked strain variation of immunopathology. In the most commonly examined mouse strain, C57BL/6 (BL/6), there is relatively mild hepatic pathology arising in a Th2-dominated cytokine environment. In contrast, CBA mice develop decisively more severe lesions largely driven by proinflammatory IL-17-producing Th17 cells. Dendritic cells (DCs) from CBA mice differ sharply with those from BL/6 mice in that they vastly over-express the C-type lectin receptor (CLR) CD209a (SIGNR5), a homolog of human DC-SIGN, which senses glycans such as those produced by schistosome eggs. Silencing of CD209a, and recent studies with CD209a KO CBA mice have shown that this receptor is crucial to induce the pathogenic Th17 cell response; indeed, CD209a KO mice display markedly reduced immunopathology akin to that seen in BL/6 mice. Mechanistically, CD209a synergizes with the related CLRs Dectin-2 and Mincle to stimulate increased DC production of IL-1ß and IL-23, necessary for pathogenic Th17 cell development. These findings denote key molecular underpinnings of disease variability based on selection and function of contrasting Th cell subsets.