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PLoS Pathogens Jul 2023Schistosomiasis, a severe parasitic disease, is primarily caused by Schistosoma mansoni, Schistosoma japonicum, or Schistosoma haematobium. Currently, praziquantel is... (Review)
Review
Schistosomiasis, a severe parasitic disease, is primarily caused by Schistosoma mansoni, Schistosoma japonicum, or Schistosoma haematobium. Currently, praziquantel is the only recommended drug for human schistosome infection. However, the lack of efficacy of praziquantel against juvenile worms and concerns about the emergence of drug resistance are driving forces behind the research for an alternative medication. Schistosomes are obligatory parasites that survive on nutrients obtained from their host. The ability of nutrient uptake depends on their physiological structure. In short, the formation and maintenance of the structure and nutrient supply are mutually reinforcing and interdependent. In this review, we focus on the structural features of the tegument, esophagus, and intestine of schistosomes and their roles in nutrient acquisition. Moreover, we introduce the significance and modes of glucose, lipids, proteins, and amino acids intake in schistosomes. We linked the schistosome structure and nutrient supply, introduced the currently emerging targets, and analyzed the current bottlenecks in the research and development of drugs and vaccines, in the hope of providing new strategies for the prevention and control of schistosomiasis.
Topics: Animals; Humans; Praziquantel; Schistosomiasis; Schistosoma japonicum; Schistosoma haematobium; Schistosoma mansoni; Eating
PubMed: 37498810
DOI: 10.1371/journal.ppat.1011498 -
Parasitology Aug 2023Bovines are important reservoir hosts of schistosomiasis, placing humans and animals in rice fields areas at risk of infection. This study reported the prevailing...
Bovines are important reservoir hosts of schistosomiasis, placing humans and animals in rice fields areas at risk of infection. This study reported the prevailing infection of zoonotic parasites from bovine feces in the rice fields adjacent to Lake Mainit, Philippines. Formalin Ethyl Acetate Sedimentation was performed on 124 bovine fecal samples from rice fields and documented eggs and cysts from seven parasites: sp., sp., coccidian oocyst and a hookworm species. Among these parasites, harboured the highest infection with a 100% prevalence rate, followed by hookworms (51.61%), (30.64%) and (12.09%), respectively. The intensity of infection of eggs per gram (MPEG = 4.19) among bovines is categorized as ‘light.’ Bovine contamination index (BCI) calculations revealed that, on average, infected bovines in rice fields excrete 104 750 eggs daily. However, across all ricefield stations, bovines were heavily infected with fascioliasis with BCI at 162 700 eggs per day. The study reports that apart from the persistent cases of schistosomiasis in the area, bovines in these rice fields are also heavily infected with fascioliasis. The study confirms the critical role of bovines as a reservoir host for continued infection of schistosomiasis, fascioliasis and other diseases in the rice fields of Lake Mainit. Immediate intervention to manage the spread of these diseases in bovines is recommended.
Topics: Humans; Animals; Cattle; Schistosoma japonicum; Schistosomiasis japonica; Parasites; Fascioliasis; Ecosystem; Lakes; Philippines; Schistosomiasis; China
PubMed: 37496395
DOI: 10.1017/S0031182023000537 -
EBioMedicine Aug 2023Schistosomiasis is a disease that significantly impacts human health in the developing world. Effective diagnostics are urgently needed for improved control of this...
BACKGROUND
Schistosomiasis is a disease that significantly impacts human health in the developing world. Effective diagnostics are urgently needed for improved control of this disease. CRISPR-based technology has rapidly accelerated the development of a revolutionary and powerful diagnostics platform, resulting in the advancement of a class of ultrasensitive, specific, cost-effective and portable diagnostics, typified by applications in COVID-19/cancer diagnosis.
METHODS
We developed CRISPR-based diagnostic platform SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing) for the detection of Schistosoma japonicum and S. mansoni by combining recombinase polymerase amplification (RPA) with CRISPR-Cas13a detection, measured via fluorescent or colorimetric readouts. We evaluated SHERLOCK assays by using 150 faecal/serum samples collected from Schistosoma-infected ARC Swiss mice (female), and 189 human faecal/serum samples obtained from a S. japonicum-endemic area in the Philippines and a S. mansoni-endemic area in Uganda.
FINDINGS
The S. japonicum SHERLOCK assay achieved 93-100% concordance with gold-standard qPCR detection across all the samples. The S. mansoni SHERLOCK assay demonstrated higher sensitivity than qPCR and was able to detect infection in mouse serum as early as 3 weeks post-infection. In human samples, S. mansoni SHERLOCK had 100% sensitivity when compared to qPCR of faecal and serum samples.
INTERPRETATION
These schistosomiasis diagnostic assays demonstrate the potential of SHERLOCK/CRISPR-based diagnostics to provide highly accurate and field-friendly point-of-care tests that could provide the next generation of diagnostic and surveillance tools for parasitic neglected tropical diseases.
FUNDING
Australian Infectious Diseases Research Centre seed grant (2022) and National Health and Medical Research Council (NHMRC) of Australia (APP1194462, APP2008433).
Topics: Humans; Female; Animals; Mice; Sensitivity and Specificity; Australia; COVID-19; Schistosomiasis; Schistosoma japonicum; COVID-19 Testing
PubMed: 37487416
DOI: 10.1016/j.ebiom.2023.104730 -
Journal of Cellular and Molecular... Aug 2023Schistosomiasis 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...
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.
Topics: Humans; Animals; Mice; Schistosoma japonicum; Macrophages, Peritoneal; Schistosomiasis japonica; Macrophages; Liver; Schistosomiasis; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 37430471
DOI: 10.1111/jcmm.17842 -
PLoS Pathogens Jul 2023Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for...
Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies for schistosomiasis. Previous treatment of S. mansoni included the use of oxamniquine (OXA), a drug that is activated by a schistosome sulfotransferase (SULT). Guided by data from X-ray crystallography and Schistosoma killing assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150610 and CIDD-0150303 as potent derivatives in vitro that kill (100%) of all three Schistosoma species at a final concentration of 71.5 μM. We evaluated the efficacy of the best OXA derivates in an in vivo model after treatment with a single dose of 100 mg/kg by oral gavage. The highest rate of worm burden reduction was achieved by CIDD -150303 (81.8%) against S. mansoni, CIDD-0149830 (80.2%) against S. haematobium and CIDD-066790 (86.7%) against S. japonicum. We have also evaluated the ability of the derivatives to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150303 demonstrated (100%) killing for all life stages at a final concentration of 143 μM in vitro and effective reduction in worm burden in vivo against S. mansoni. To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150303 and CIDD-0150610 demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we fine tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg/kg by oral gavage with co-dose of PZQ + CIDD-0150303 reduced the worm burden of PZQ resistant parasites in an animal model by 90.8%. Therefore, we conclude that CIDD-0150303, CIDD-0149830 and CIDD-066790 are novel drugs that overcome some of PZQ limitations, and CIDD-0150303 can be used with PZQ in combination therapy.
Topics: Animals; Humans; Praziquantel; Oxamniquine; Schistosomiasis; Schistosoma mansoni; Combined Modality Therapy; Neglected Diseases; Schistosomiasis mansoni; Anthelmintics
PubMed: 37428793
DOI: 10.1371/journal.ppat.1011018 -
PLoS Neglected Tropical Diseases Jul 2023Praziquantel (PZQ) has been the first line antischistosomal drug for all species of Schistosoma, and the only available drug for schistosomiasis japonica, without any...
Small change, big difference: A promising praziquantel derivative designated P96 with broad-spectrum antischistosomal activity for chemotherapy of schistosomiasis japonica.
BACKGROUND
Praziquantel (PZQ) has been the first line antischistosomal drug for all species of Schistosoma, and the only available drug for schistosomiasis japonica, without any alternative drugs since the 1980s. However, PZQ cannot prevent reinfection, and cannot cure schistosomiasis thoroughly because of its poor activity against juvenile schistosomes. In addition, reliance on a single drug is extremely dangerous, the development and spread of resistance to PZQ is becoming a great concern. Therefore, development of novel drug candidates for treatment and control of schistosomiasis is urgently needed.
METHODOLOGYS/PRINCIPAL FINDINGS
One of the PZQ derivative christened P96 with the substitution of cyclohexyl by cyclopentyl was synthesized by School of Pharmaceutical Sciences of Shandong University. We investigated the in vitro and in vivo activities of P96 against different developmental stages of S. japonicum. Parasitological studies and scanning electron microscopy were used to study the primary action characteristics of P96 in vitro. Both mouse and rabbit models were employed to evaluate schistosomicidal efficacy of P96 in vivo. Besides calculation of worm reduction rate and egg reduction rate, quantitative real-time PCR was used to evaluate the in vivo antischistosomal activity of P96 at molecular level. In vitro, after 24h exposure, P96 demonstrated the highest activities against both juvenile and adult worm of S. japonicum in comparison to PZQ. The antischistosomal efficacy was concentration-dependent, with P96 at 50μM demonstrating the most evident schistosomicidal effect. Scanning electron microscopy demonstrated that P96 caused more severe damages to schistosomula and adult worm tegument compared to PZQ. In vivo, our results showed that P96 was effective against S. japonicum at all developmental stages. Notably, its efficacy against young stage worms was significantly improved compared to PZQ. Moreover, P96 retained the high activity comparable to PZQ against the adult worm of S. japonicum.
CONCLUSIONS
P96 is a promising drug candidate for chemotherapy of schistosomiasis japonica, which has broad spectrum of action against various developmental stage, potentially addressing the deficiency of PZQ. It might be promoted as a drug candidate for use either alone or in combination with PZQ for the treatment of schistosomiasis.
Topics: Animals; Mice; Rabbits; Microscopy, Electron, Scanning; Praziquantel; Schistosoma japonicum; Schistosomiasis japonica; Schistosomicides
PubMed: 37410790
DOI: 10.1371/journal.pntd.0011215 -
International Journal For Parasitology Oct 2023Eggs laid by mature female schistosomes are primarily responsible for the pathogenesis of schistosomiasis and critical for transmission. Consequently, elucidating the...
Eggs laid by mature female schistosomes are primarily responsible for the pathogenesis of schistosomiasis and critical for transmission. Consequently, elucidating the mechanism of sexual maturation as well as egg production may lead to new strategies for the control of schistosomiasis. MicroRNAs (miRNAs) are involved in multiple biological processes including reproduction in many organisms, yet their roles have not been well characterized in schistosomes. Here, we investigated microRNA-1 (miR-1), which was downregulated gradually in both male and female Schistosoma japonicum after they reached sexually maturity. The expression of miR-1, as shown with quantitative reverse transcription PCR (qRT-PCR), was lower in the reproductive organs of adult females compared with the somatic tissues. Overexpression of miR-1 in adult worms destroyed the morphological architecture of reproductive organs and reduced the subsequent oviposition, which may be due to the activation of apoptosis pathways. Through in silico analysis, 34 potential target genes of miR-1 were identified, including five ribosomal protein genes, called rp-s13, rp-l7ae, rp-l14, rp-l11 and rp-s24e. In vitro dual-luciferase reporter gene assays and miRNA overexpression experiments further validated that these ribosomal protein genes were directly regulated by miR-1. In contrast to the gene expression of miR-1, qRT-PCR and in situ hybridization experiments demonstrated these ribosomal protein genes were enriched in the sexual organs of adult females. Using RNA interference to silence the ribosomal protein genes in different developmental stages in a mouse model system, we demonstrated that these miR-1 target genes not only participated in the reproductive development of S. japonicum, but also were required for the growth and survival of the parasite in the early developmental stages. Taken together, our data suggested that miR-1 may affect the growth, reproduction and oviposition of S. japonicum by targeting the ribosomal protein genes, which provides insights for exploration of new anti-schistosome strategies.
Topics: Mice; Animals; Female; Male; Schistosoma japonicum; MicroRNAs; Ribosomal Proteins; Reproduction; Schistosomiasis; Biological Phenomena; Schistosomiasis japonica
PubMed: 37355197
DOI: 10.1016/j.ijpara.2023.03.007 -
International Journal For Parasitology.... Aug 2023is the obligate intermediate host of , highlighting the medical importance of interrupting this unique and long-standing parasite-host interaction in controlling...
is the obligate intermediate host of , highlighting the medical importance of interrupting this unique and long-standing parasite-host interaction in controlling schistosomiasis transmission. It has been reported that a catfish trematode sp. could have the potential to function as an effective anti-schistosomal agent in the snail host. However, the feasibility of this eco-friendly biological control strategy should be comprehensively investigated and evaluated in endemic areas for schistosomiasis. In this study, a field survey was conducted from 2012 to 2016 in the marshlands of Poyang Lake, which is one of the highly endemic regions for schistosomiasis in China. Results showed that more than half of (65.79%) were infected with sp., and the average intensity of infection was 14.21 per fish. And the average infection rate of sp. in is 1.11%. These findings indicated that there are abundant biological resources for the implementation of this biology control strategy in the marshlands of Poyang Lake. The data presented here provide solid evidences for the practical application of this biological control strategy, thereby contributing to achieving the goals of the elimination of schistosomiasis.
PubMed: 37215532
DOI: 10.1016/j.ijppaw.2023.04.013