Search Results (10)

The expansion of drug resistant parasites sheds a serious concern on several neglected parasitic diseases. Our recent results on cancer led us to envision the use of peptide-alkoxyamines as a highly selective and efficient new drug against schistosome adult worms, the etiological agents of schistosomiasis. Indeed, the peptide tag of the hybrid compounds can be hydrolyzed by worm’s digestive enzymes to afford a highly labile alkoxyamine which homolyzes spontaneously and instantaneously into radicals—which are then used as a drug against Schistosome adult parasites. This approach is nicely summarized as digging their graves with their forks. Several hybrid peptide-alkoxyamines were prepared and clearly showed an activity: two of the tested compounds kill 50% of the parasites in two hours at a concentration of 100 µg/mL. Importantly, the peptide and alkoxyamine fragments that are unable to generate alkyl radicals display no activity. This strong evidence validates the proposed mechanism: a specific activation of the prodrugs by the parasite proteases leading to parasite death through in situ alkyl radical generation. Full article

Malaria and schistosomiasis are two of the neglected tropical diseases that persistently wreak havoc worldwide. Although many antimalarial drugs such as chloroquine are readily available, the emergence of drug resistance necessitates the development of new therapies to combat this disease. Conversely, Praziquantel (PZQ) remains the sole effective drug against schistosomiasis, but its extensive use raises concerns about the potential for drug resistance to develop. In this project, the concept of molecular hybridization was used as a strategy to design the synthesis of new molecular hybrids with potential antimalarial and antischistosomal activity. A total of seventeen molecular hybrids and two PZQ analogues were prepared by coupling 6-alkylpraziquanamines with cinnamic acids and cyclohexane carboxylic acid, respectively. The synthesised compounds were evaluated for their antimalarial and antischistosomal activity; while all of the above compounds were inactive against Plasmodium falciparum (IC₅₀ > 6 µM), many were active against schistosomiasis with four particular compounds exhibiting up to 100% activity against newly transformed schistosomula and adult worms at 50 µM. Compared to PZQ, the reference drug, the activity of which is 91.7% at 1 µM, one particular molecular hybrid, compound 32, which bears a para-isopropyl group on the cinnamic acid moiety, exhibited a notable activity at 10 µM (78.2% activity). This compound has emerged as the front runner candidate that might, after further optimization, hold promise as a potential lead compound in the fight against schistosomiasis. Full article

Schistosomiasis is one of the leading neglected tropical diseases in sub-Saharan Africa. Recorded case numbers of this chronic and debilitating helminth disease indicate Nigeria to be the most endemic country within this region. National control efforts have focused intensively on restricting human contact with freshwater sources of intermediate host snails. However, limited attention has been paid to the role of livestock as reservoir hosts and the prevalence of transmission of schistosomes to humans via farmed animals. The West African nations of Mali, Senegal, and the neighbouring Niger, Benin, and Cameroon have all reported the hybridization of the closely related species of Schistosoma haematobium, which infects humans, and S. bovis, which infects cattle. As these countries share the Niger and Benue rivers, with their tributaries, there is a distinct possibility of aquatic snails infected with hybrid schistosomes migrating to become established in the Nigerian river system. Here, we report on the current state of research in Nigeria that aims to elucidate key aspects of zoonotic schistosomiasis epidemiology. Factors promoting the hybridization of Schistosoma species are highlighted, and how available control measures can be optimized to address the emergence of schistosome hybrids is discussed. Full article

The freshwater snail genus Bulinus plays a vital role in transmitting parasites of the Schistosoma haematobium group. A hybrid schistosome between S. haematobium and S. mattheei has been recently detected using DNA-based identification methods in school children along the Lake Malawi shoreline in Mangochi District. This finding raised the need for contemporary revaluation of local interactions between schistosomes and snails, with a particular focus on snail species within the Bulinus africanus group. In 2017 and 2018, malacological surveys sampled several freshwater sites in Mangochi District. Collected snails (n = 250) were characterised using cytochrome oxidase subunit 1 gene (cox1), with DNA barcoding of the ‘Folmer’ region and a rapid PCR-RFLP typing assay with double digestion with HaeIII and SacI restriction enzymes. DNA cox1 sequence analysis, with phylogenetic tree construction, suggested the presence of at least three B. africanus group taxa in Lake Malawi, B. globosus, alongside first reports of B. africanus and B. angolensis, which can be differentiated by PCR-RFLP methods. In addition, a total of 30 of the 106 B. africanus group snails (28.30%) were positive to the Schistosoma-specific screen using real-time PCR methods. This study provides new insight into the recent changes in the epidemiology of urogenital schistosomiasis as likely driven by a new diversity of B. africanus group snails within the Lake. Full article

Oxamniquine (OXA) is a prodrug activated by a sulfotransferase (SULT) that was only active against Schistosoma mansoni. We have reengineered OXA to be effective against S. haematobium and S. japonicum. Three derivatives stand out, CIDD-0066790, CIDD-0072229, and CIDD-0149830 as they kill all three major human schistosome species. However, questions remain. Is the OXA mode of action conserved in derivatives? RNA-interference experiments demonstrate that knockdown of the SmSULT, ShSULT, and SjSULT results in resistance to CIDD-0066790. Confirming that the OXA-derivative mode of action is conserved. Next is the level of expression of the schistosome SULTs in each species, as well as changes in SULT expression throughout development in S. mansoni. Using multiple tools, our data show that SmSULT has higher expression compared to ShSULT and SjSULT. Third, is the localization of SULT in the adult, multicellular eucaryotic schistosome species. We utilized fluorescence in situ hybridization and uptake of radiolabeled OXA to determine that multiple cell types throughout the adult schistosome worm express SULT. Thus, we hypothesize the ability of many cells to express the sulfotransferase accounts for the ability of the OXA derivatives to kill adult worms. Our studies demonstrate that the OXA derivatives are able to kill all three human schistosome species and thus will be a useful complement to PZQ. Full article

About 250 million people affected, 779 million people at risk of infection, and 440 million people with residual morbidity are globally attributable to schistosomiasis. Highly sensitive and specific, simple, and fast to perform diagnostics are required for detecting trace infections, and applications in resource-poor settings and large-scale assessments. Research assessing isothermal diagnoses of S. japonicum, S. haematobium, S. mansoni, mixed infections, and schistosomal hybrids among clinical human specimens was investigated. Loop-mediated isothermal amplification (LAMP), recombinase polymerase amplification (RPA) and combined techniques were identified. Both LAMP and RPA reached species-dependent 100% sensitivity, and detection levels within femtogram and nanogram amounts for pure and hybridale breeds. Cross-reactivity among Schistosoma species and co-endemic pathogens was rare, though research on diagnostic markers and primer optimization should continue. Operating with ready-to-use lyophilized reagents, simplified and inexpensive nucleic acid extraction, tolerability to likely inhibitors, and enzyme stability at ambient temperature is advantageous. RPA performed optimal at 35–39 °C within 5–10 min. while LAMP operated at 61–65 °C for up to 120 min.; properties are preferable over assays requiring expensive laboratory equipment. DNA degradation could be prevented by stabilizing substances. A limitation throughout warranting future research is the small sample size reaching a few hundred participants at the maximum. Isothermal diagnostics are highly valuable in detecting trace infections seen subsequent to chemotherapeutic treatment, and among apparently healthy individuals, both constituting likely sources of ongoing pathogen transmission. Its expansion to the vaccine field for assessing parasitological trial endpoints could be considered. Full article

Background: Schistosomiasis is a major poverty-related disease caused by dioecious parasitic flatworms of the genus Schistosoma with a health impact on both humans and animals. Hybrids of human urogenital schistosome and bovine intestinal schistosome have been reported in humans in several of Nigeria’s neighboring West African countries. No empirical studies have been carried out on the genomic diversity of Schistosoma haematobium in Nigeria. Here, we present novel data on the presence and prevalence of hybrids and the population genetic structure of S. haematobium. Methods: 165 Schistosoma-positive urine samples were obtained from 12 sampling sites in Nigeria. Schistosoma haematobium eggs from each sample were hatched and each individual miracidium was picked and preserved in Whatman^® FTA cards for genomic analysis. Approximately 1364 parasites were molecularly characterized by rapid diagnostic multiplex polymerase chain reaction (RD-PCR) for mitochondrial DNA gene (Cox1 mtDNA) and a subset of 1136 miracidia were genotyped using a panel of 18 microsatellite markers. Results: No significant difference was observed in the population genetic diversity (p > 0.05), though a significant difference was observed in the allelic richness of the sites except sites 7, 8, and 9 (p < 0.05). Moreover, we observed two clusters of populations: west (populations 1–4) and east (populations 7–12). Of the 1364 miracidia genotyped, 1212 (89%) showed an S. bovis Cox1 profile and 152 (11%) showed an S. haematobium cox1 profile. All parasites showed an S. bovis Cox1 profile except for some at sites 3 and 4. Schistosoma miracidia full genotyping showed 59.3% of the S. bovis ITS2 allele. Conclusions: This study provides novel insight into hybridization and population genetic structure of S. haematobium in Nigeria. Our findings suggest that S. haematobium x S. bovis hybrids are common in Nigeria. More genomic studies on both human- and animal-infecting parasites are needed to ascertain the role of animals in schistosome transmission. Full article

Causal agents of schistosomiasis are dioecious, digenean schistosomes affecting mankind in 76 countries. Preventive measures are manifold but need to be complemented by vaccination for long-term protection; vaccine candidates in advanced pre-clinical/clinical stages include Sm14, Sm-TSP-2/Sm-TSP-2Al^®, Smp80/SchistoShield^®, and Sh28GST/Bilhvax^®. Natural and anthropogenic changes impact on breaking species isolation barriers favoring introgressive hybridization, i.e., allelic exchange among gene pools of sympatric, interbreeding species leading to instant large genetic diversity. Phylogenetic distance matters, thus the less species differ phylogenetically the more likely they hybridize. PubMed and Embase databases were searched for publications limited to hybridale confirmation by mitochondrial cytochrome c oxidase (COX) and/or nuclear ribosomal internal transcribed spacer (ITS). Human schistosomal hybrids are predominantly reported from West Africa with clustering in the Senegal River Basin, and scattering to Europe, Central and Eastern Africa. Noteworthy is the dominance of Schistosoma haematobium interbreeding with human and veterinary species leading due to hybrid vigor to extinction and homogenization as seen for S. guineensis in Cameroon and S. haematobium in Niger, respectively. Heterosis seems to advantage S. haematobium/S. bovis interbreeds with dominant S. haematobium-ITS/S. bovis-COX1 profile to spread from West to East Africa and reoccur in France. S. haematobium/S. mansoni interactions seen among Senegalese and Côte d’Ivoirian children are unexpected due to their high phylogenetic distance. Detecting pure S. bovis and S. bovis/S. curassoni crosses capable of infecting humans observed in Corsica and Côte d’Ivoire, and Niger, respectively, is worrisome. Taken together, species hybridization urges control and preventive measures targeting human and veterinary sectors in line with the One-Health concept to be complemented by vaccination protecting against transmission, infection, and disease recurrence. Functional and structural diversity of naturally occurring human schistosomal hybrids may impact current vaccine candidates requiring further research including natural history studies in endemic areas targeted for clinical trials. Full article

Schistosomiasis is a disease of great medical and veterinary importance in tropical and subtropical regions caused by different species of parasitic flatworms of the genus Schistosoma. The emergence of natural hybrids of schistosomes indicate the risk of possible infection to humans and their zoonotic potential, specifically for Schistosoma haematobium and S. bovis. Hybrid schistosomes have the potential to replace existing species, generate new resistances, pathologies and extending host ranges. Hybrids may also confuse the serological, molecular and parasitological diagnosis. Currently, LAMP technology based on detection of nucleic acids is used for detection of many agents, including schistosomes. Here, we evaluate our previously developed species-specific LAMP assays for S. haematobium, S. mansoni, S. bovis and also the genus-specific LAMP for the simultaneous detection of several Schistosoma species against both DNA from pure and, for the first time, S. haematobium x S. bovis hybrids. Proper operation was evaluated with DNA from hybrid schistosomes and with human urine samples artificially contaminated with parasites’ DNA. LAMP was performed with and without prior DNA extraction. The genus-specific LAMP properly amplified pure Schistosoma species and different S. haematobium-S. bovis hybrids with different sensitivity. The Schistosoma spp.-LAMP method is potentially adaptable for field diagnosis and disease surveillance in schistosomiasis endemic areas where human infections by schistosome hybrids are increasingly common. Full article

Schistosomiasis is recognized as a tropical disease of considerable public health importance, but domestic livestock infections due to Schistosoma japonicum, S. bovis, S. mattheei and S. curassoni are often overlooked causes of significant animal morbidity and mortality in Asia and Africa. In addition, whereas schistosomiasis japonica is recognized as an important zoonosis in China and the Philippines, reports of viable schistosome hybrids between animal livestock species and S. haematobium point to an underappreciated zoonotic component of transmission in Africa as well. Anti-schistosome vaccines for animal use have long been advocated as part of the solution to schistosomiasis control, benefitting humans and animals and improving the local economy, features aligning with the One Health concept synergizing human and animal health. We review the history of animal vaccines for schistosomiasis from the early days of irradiated larvae and then consider the recombinant DNA technology revolution and its impact in developing schistosome vaccines that followed. We evaluate the major candidates tested in livestock, including the glutathione S-transferases, paramyosin and triose-phosphate isomerase, and summarize some of the future challenges that need to be overcome to design and deliver effective anti-schistosome vaccines that will complement current control options to achieve and sustain future elimination goals. Full article