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Concept: Strigeidida

153

Upon infection with Schistosoma, antibody responses are mounted that are largely directed against glycans. Over the last few years significant progress has been made in characterizing the antigenic properties of N-glycans of Schistosoma mansoni. Despite also being abundantly expressed by schistosomes, much less is understood about O-glycans and antibody responses to these have not yet been systematically analyzed. Antibody binding to schistosome glycans can be analyzed efficiently and quantitatively using glycan microarrays, but O-glycan array construction and exploration is lagging behind because no universal O-glycanase is available, and release of O-glycans has been dependent on chemical methods. Recently, a modified hydrazinolysis method has been developed that allows the release of O-glycans with free reducing termini and limited degradation, and we applied this method to obtain O-glycans from different S. mansoni life stages. Two-dimensional HPLC separation of 2-aminobenzoic acid-labeled O-glycans generated 362 O-glycan-containing fractions that were printed on an epoxide-modified glass slide, thereby generating the first shotgun O-glycan microarray containing naturally occurring schistosome O-glycans. Monoclonal antibodies and mass spectrometry showed that the O-glycan microarray contains well-known antigenic glycan motifs as well as numerous other, potentially novel, antibody targets. Incubations of the microarrays with sera from Schistosoma-infected humans showed substantial antibody responses to O-glycans in addition to those observed to the previously investigated N- and glycosphingolipid glycans. This underlines the importance of the inclusion of these often schistosome-specific O-glycans in glycan antigen studies and indicates that O-glycans contain novel antigenic motifs that have potential for use in diagnostic methods and studies aiming at the discovery of vaccine targets.

Concepts: Immune system, Antibody, Schistosomiasis, Schistosoma mansoni, Schistosoma, Digenea, Antigen, Strigeidida

144

Symptomatic acute schistosomiasis mansoni is a systemic hypersensitivity reaction against the migrating schistosomula and mature eggs after a primary infection. The mechanisms involved in the pathogenesis of acute schistosomiasis are not fully elucidated. Osteopontin has been implicated in granulomatous reactions and in acute hepatic injury. Our aims were to evaluate if osteopontin plays a role in acute Schistosoma mansoni infection in both human and experimentally infected mice and if circulating OPN levels could be a novel biomarker of this infection.

Concepts: Immune system, Schistosomiasis, Schistosoma mansoni, Schistosoma, Digenea, Strigeidida, Oxamniquine

143

Intestinal schistosomiasis due to Schistosoma mansoni was first reported in Oman in 1979. We describe the trend in parasitological and serological prevalence of human infection with S. mansoni in the endemic area over the period 1982-2014, and the compliance of data generated by the national monitoring and evaluation system with schistosomiasis elimination criteria set by the Ministry of Health of Oman.

Concepts: Epidemiology, Schistosomiasis, Schistosoma mansoni, Schistosoma, Digenea, Strigeidida, Oxamniquine

140

The antischistosomal pro-drug oxamniquine is activated by a sulfotransferase (SULT) in the human parasite Schistosoma mansoni Of the three main human blood fluke species, only S. mansoni is sensitive to oxamniquine therapy despite the presence of SULT orthologs in S. haematobium and S. japonicum The reason for this species-specific drug action has remained a mystery for decades. Here we present the crystal structures of S. haematobium and S. japonicum SULTs, including S. haematobium SULT in complex with oxamniquine. Our finding that all three enzymes show activity toward oxamniquine in vitro reveals differences in catalytic efficiency that implicate kinetics as the determinant for species-specific toxicity. These results support the initiative for designing oxamniquine derivatives to treat infection caused by all species of blood fluke to combat emerging resistance to current therapy.

Concepts: Parasites, Schistosomiasis, Schistosoma mansoni, Schistosoma, Digenea, Schistosoma haematobium, Schistosoma japonicum, Strigeidida

27

Up to date, schistosomiasis is still prevalent worldwide. It is estimated that more than 200 million individuals are infected, and 120 million suffer from clinical morbidity. Facing such huge cases of schistosomiasis, only heavy reliance on a single praziquantel for schistosomiasis control does not adapt and may promote the selection and spread of drug-resistant parasites. Therefore, it is an urgent need to develop the new antischistosomal drug. In 2008-2009, the antimalarial drug mefloquine, an arylaminoalcohol compound, has been found to be effective against schistosomes. According to the experimental studies, the deepest impression on the antischistosomal properties of mefloquine can be summarized as following points: (1) single dose of mefloquine possesses potential effect against three major species of schistosomes (Schistosoma mansoni, Schistosoma haematobium, and Schistosoma japonicum) infecting humans; (2) the drug displays similar effects against developing stages of juvenile and adult schistosomes, which are superior to that of artemisinins and praziquantel; (3) in vitro mefloquine exerts direct killing effect on juvenile and adult schistosomes, while in vivo, the efficacy of the drug is independent to host immune response, (4) mefloquine causes extensive and severe morphological, histopathological, and ultrastructural damage to adult and juvenile schistosomes, particularly, the worm tegument, musculature, gut, and vitelline glands of female worms are the key sites attacked by the drug; (5) combined treatment with mefloquine and praziquantel, or artemisinins shows synergistic effect against schistosome in experimental therapy,while in initially clinical trial, mefloquine in combination with artesunate also exhibits higher cure rates against schistosomiasis hematobia and schistosomiasis mansoni, and (6) several mefloquine-related arylmethanols exhibit potential effect against schistosomes in vivo, which is a useful clue helpful for development of new antischistosomal compound. In the present review, we have summarized the major results published in recent years, and the significance as well as the prospect for the future study of mefloquine have been discussed briefly.

Concepts: Parasites, Schistosomiasis, Schistosoma mansoni, Schistosoma, Digenea, Schistosoma haematobium, Schistosoma japonicum, Strigeidida

26

Schistosomiasis is a chronic parasitic disease of humans, with two species primarily causing the intestinal infection: Schistosoma mansoni and Schistosoma japonicum. Traditionally, diagnosis of schistosomiasis is achieved through direct visualization of eggs in faeces using techniques that lack the sensitivity required to detect all infections, especially in areas of low endemicity. A recently developed method termed Helmintex™ is a very sensitive technique for detection of Schistosoma eggs and exhibits 100% sensitivity at 1.3 eggs per gram of faeces, enough to detect even low-level infections. The Helminthex™ method is based on the interaction of magnetic microspheres and schistosome eggs. Further understanding the underlying egg-microsphere interactions would enable a targeted optimization of egg-particle binding and may thus enable a significant improvement of the Helmintex™ method and diagnostic sensitivity in areas with low infection rates. We investigated the magnetic properties of S. mansoni and S. japonicum eggs and their interactions with microspheres with different magnetic properties and surface functionalization. Eggs of both species exhibited higher binding affinity to the magnetic microspheres than the non-magnetic microspheres. Binding efficiency was further enhanced if the particles were coated with streptavidin. Schistosoma japonicum eggs bound more microspheres compared with S. mansoni. However, distinct differences within eggs of each species were also observed when the distribution of the number of microspheres bound per egg was modeled with double Poisson distributions. Using this approach, both S. japonicum and S. mansoni eggs fell into two groups, one having greater affinity for magnetic microspheres than the other, indicating that not all eggs of a species exhibit the same binding affinity. Our observations suggest that interaction between the microspheres and eggs is more likely to be related to surface charge-based electrostatic interactions between eggs and magnetic iron oxide rather than through a direct magnetic interaction.

Concepts: Parasites, Schistosomiasis, Schistosoma mansoni, Schistosoma, Digenea, Magnetism, Schistosoma japonicum, Strigeidida

24

Preventive chemotherapy with praziquantel is the mainstay of schistosomiasis control. However, drug resistance is an imminent threat, particularly with large-scale administration of praziquantel, in addition to much less efficacy against young schistosomes. Several biological activities of limonin have been explored such as insecticidal, insect antifeedant, and growth-regulating activity on insects as well as antimalarial, antiviral, anticancer, cholesterol-lowering, and antioxidant activities. This study investigates limonin as an alternative antischistosomal compound using two novel, single, oral dose regimens. In the current work, the therapeutic efficacy of different limonin dosing protocols was evaluated in experimentally infected mice harboring Schistosoma mansoni (Egyptian strain) juvenile or adult stages. Oral administration of limonin in a single dose of 50 or 100 mg/kg on day 21 post-infection (p.i.) resulted in a significant worm burden reduction of 70.0 and 83.33 %, respectively. The same dose given on day 56 p.i. reduced total worm burdens by 41.09 and 60.27 %, respectively. In addition, significant reductions of 34.90 and 47.16 % in the hepatic and 46.67 and 56.1 % in the intestinal tissue egg loads, respectively, associated with significant alterations in the oogram pattern with elevated dead egg levels. Limonin produced ameliorations of hepatic pathology with reduction in dimensions and number of granulomas. Limonin also produced a variety of tegumental alterations in treated worms including tubercular disruption, edema, blebbing, and ulcerations. Results obtained by this work elucidated promising limonin bioactivity against S. mansoni juvenile and adult stages and provided a basis for subsequent experimental and clinical trials.

Concepts: Pharmacology, Insect, Schistosomiasis, Schistosoma mansoni, Schistosoma, Digenea, Hemozoin, Strigeidida

24

Praziquantel (PZQ) is the only available drug to treat schistosomiasis, and since its large scale use might be associated with the onset of resistance, new antischistosomal drugs should be developed. A series of 26 synthetic tetraazamacrocyclic derivatives and their metal complexes were synthesized, characterized, and screened for antischistosomal activity applying a phased screening program. The compounds were first screened against newly transformed schistosomula (NTS) of harvested Schistosoma mansoni cercariae, then against adult worms, and finally in vivo using the mouse model of S. mansoni At a concentration of 33 μM, a total of 13 compounds resulted in mortality of NTS at the 61% to 100% level. Five of these showing 100% inhibition at 10 μM were selected for further screening for IC50 determination against both NTS and adult worms. Against NTS, all 5 compounds showed IC50 values comparable to that of standard drug PZQ (0.87 to 9.65 μM vs 2.20 μM for PZQ). Three of these, which are bisquinoline derivative of cyclen and its Fe(2+)- and Mn(2+)-complexes, showed micromolar IC50 values (1.62 μM, 1.34 μM and 4.12 μM, respectively vs 0.10 μM for PZQ) against adult worms. In vivo, the worm burden reductions were 12.3%, 88.4% and 74.8%, respectively at a 400 mg/kg single oral dose. The Fe(2+)-complex exhibited activity in vivo comparable to that of PZQ pointing to the discovery of a novel drug lead for schistosomiasis.

Concepts: Schistosomiasis, Schistosoma mansoni, Schistosoma, Digenea, Praziquantel, Antimony, Strigeidida, Oxamniquine

23

Schistosomiasis is a major public health problem worldwide, especially in poor communities. Since praziquantel is currently the only drug available to treat schistosomiasis, there is an urgent need to identify new antischistosomal drugs. Nerolidol is a sesquiterpene present as an essential oil in several plants, and it has been approved by the US Food and Drug Administration. In this study, we evaluated the in vivo antischistosomal activity of nerolidol in a mouse model of schistosomiasis infected with either adult or juvenile stages of Schistosoma mansoni. A single dose of nerolidol (100, 200 or 400 mg/kg) administered orally to mice infected with adult schistosomes resulted in a reduction in the worm burden and egg production. The treatment with the highest dose of nerolidol (400 mg/kg) significantly caused a total worm burden reduction of 70.06% (P<0.001). In addition, the technique of quantitative and qualitative oograms showed that a single dose of 400 mg/kg achieved immature egg reductions of 84.6% (P<0.001). In feces samples, the Kato-Katz method also revealed a reduction of 75.2% of eggs per gram at a dose of 400 mg/kg (P<0.001). Furthermore, scanning electron microscopy revealed that nerolidol-mediated worm killing was associated with tegumental damage. In contrast to the activity against adult S. mansoni infections, oral treatment with nerolidol 400 mg/kg had low efficacy in mice harboring juvenile schistosomes. Since nerolidol is already in use globally as a food additive and has a safety record, evaluation of this natural compound's potential for the treatment of schistosomiasis could be entirely cost-effective in the near future.

Concepts: Schistosomiasis, Schistosoma mansoni, Schistosoma, Digenea, Strigeidida

2

Parasitic diseases affect millions of people worldwide, causing debilitating illnesses and death. Rapid and cost-effective approaches to detect parasites are needed, especially in resource-limited settings. A common signature of parasitic diseases is the release of specific proteases by the parasites at multiple stages during their life cycles. To this end, we engineered several modular Escherichia coli and Bacillus subtilis whole-cell-based biosensors which incorporate an interchangeable protease recognition motif into their designs. Herein, we describe how several of our engineered biosensors have been applied to detect the presence and activity of elastase, an enzyme released by the cercarial larvae stage of Schistosoma mansoni. Collectively, S. mansoni and several other schistosomes are responsible for the infection of an estimated 200 million people worldwide. Since our biosensors are maintained in lyophilised cells, they could be applied for the detection of S. mansoni and other parasites in settings without reliable cold chain access.

Concepts: Bacteria, Parasites, Schistosomiasis, Schistosoma mansoni, Schistosoma, Digenea, Protease, Strigeidida