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The Journal of Biological Chemistry Jan 2024Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a...
Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently needed, as while PZQ is broadly effective it suffers from several limitations including poor efficacy against juvenile worms, which may prevent it from being completely curative. An old compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). However, host side effects caused by benzodiazepines preclude development of MCLZ as a drug and MCLZ lacks an identified parasite target to catalyze rational drug design for engineering out human host activity. Here, we identify a transient receptor potential ion channel of the melastatin subfamily, named TRPM, as a parasite target of MCLZ. MCLZ potently activates Schistosoma mansoni TRPM through engagement of a binding pocket within the voltage-sensor-like domain of the ion channel to cause worm paralysis, tissue depolarization, and surface damage. TRPM reproduces all known features of MCLZ action on schistosomes, including a lower activity versus Schistosoma japonicum, which is explained by a polymorphism within this voltage-sensor-like domain-binding pocket. TRPM is distinct from the TRP channel targeted by PZQ (TRPM), with both anthelmintic chemotypes targeting unique parasite TRPM paralogs. This advances TRPM as a novel druggable target that could circumvent any target-based resistance emerging in response to current mass drug administration campaigns centered on PZQ.
Topics: Animals; Humans; Anthelmintics; Benzodiazepines; Benzodiazepinones; Clonazepam; Praziquantel; Schistosoma mansoni; Schistosomiasis mansoni; TRPM Cation Channels
PubMed: 38043794
DOI: 10.1016/j.jbc.2023.105528 -
Scientific Reports Jan 2024Schistosoma mekongi, a significant schistosome parasite, has various life stages, including egg, cercaria, female, and male, that play crucial roles in the complex life...
Schistosoma mekongi, a significant schistosome parasite, has various life stages, including egg, cercaria, female, and male, that play crucial roles in the complex life cycle. This study aimed to explore the microRNA (miRNA) profiles across these developmental stages to understand their potential functions and evolutionary significance, which have not been studied. Pre-processed sequencing reads of small RNA (sRNA) were obtained, and annotations were performed against the S. japonicum reference miRNA database. Results indicated marked variations in miRNA profiles across different life stages, with notable similarities observed between female and male S. mekongi. Principal Coordinate Analysis (PCoA) and unsupervised clustering revealed distinct miRNA signatures for each stage. Gene ontology (GO) analysis unveiled the potential roles of these miRNAs in various biological processes. The differential expression of specific miRNAs was prominent across stages, suggesting their involvement in crucial developmental processes. Furthermore, orthologous miRNA analysis against various worm species revealed distinct presence-absence patterns, providing insights into the evolutionary relationships of these miRNAs. In conclusion, this comprehensive investigation into the miRNA profiles of S. mekongi offers valuable insights into the functional and evolutionary aspects of miRNAs in schistosome biology.
Topics: Animals; Male; Female; Schistosoma japonicum; MicroRNAs; Life Cycle Stages; RNA, Helminth
PubMed: 38281987
DOI: 10.1038/s41598-024-52835-5 -
PLoS Neglected Tropical Diseases Nov 2023Schistosomiasis is one of the most important neglected tropical infectious diseases to overcome and the primary cause of its pathogenesis is ectopic maturation of the...
BACKGROUND
Schistosomiasis is one of the most important neglected tropical infectious diseases to overcome and the primary cause of its pathogenesis is ectopic maturation of the parasite eggs. Uptake of cholesteryl ester from the host high-density lipoprotein (HDL) is a key in this process in Schistosoma japonicum and CD36-related protein (CD36RP) has been identified as the receptor for this reaction. Antibody against the extracellular domain of CD36RP (Ex160) efficiently blocked the HDL cholesteryl ester uptake and the egg embryonation in vitro. However, whether Ex160 immunization could efficiently raise proper antibody responses to sufficiently block HDL cholesteryl ester uptake and the egg embryonation to protect host in vivo is very interesting but unknown.
METHODOLOGY/PRINCIPAL FINDINGS
In this study, rabbits were immunized with the recombinant Ex160 peptide (rEx160) to evaluate its anti-pathogenic vaccine potential. Immunization with rEx160 induced consistent anti-Ex160 IgG antibody and significant reduction in development of the liver granulomatosis lesions associated with suppressed intrahepatic maturation of the schistosome eggs. The immunization with rEx160 rescued reduction of serum HDL by the infection without changing its size distribution, being consistent with interference of the HDL lipid uptake by the parasites or their eggs by antibody against Ex160 in in vitro culture.
CONCLUSIONS/SIGNIFICANCE
The results demonstrated that vaccination strategy against nutritional supply pathway of the parasite is effective for reducing its pathogenesis.
Topics: Animals; Rabbits; Schistosomiasis japonica; Schistosoma japonicum; Lipoproteins, HDL; Vaccination
PubMed: 38019787
DOI: 10.1371/journal.pntd.0011749 -
Parasites & Vectors Feb 2024Timely diagnosis of Toxoplasma gondii infection is necessary to prevent and control toxoplasmosis transmission. The gold immunochromatographic assay (GICA) is a means of...
BACKGROUND
Timely diagnosis of Toxoplasma gondii infection is necessary to prevent and control toxoplasmosis transmission. The gold immunochromatographic assay (GICA) is a means of rapidly detecting pathogen in samples. GICA-based diagnostic methods have been developed to accurately detect pathogens with high sensitivity and specificity, and their application in T. gondii diagnosis is expected to yield good results.
METHODS
Colloidal gold test strips were produced using T. gondii C-terminal truncated apical membrane antigen 1 (AMA1C). Colloidal gold-AMA1C and colloidal gold-murine protein conjugate were synthesized under optimal conditions. A nitrocellulose membrane was treated with AMA1C and goat anti-mouse antibody as the test line and control line, respectively. In total, 90 cat serum samples were tested using AMA1C-GICA and a commercial enzyme linked immunosorbent assay (ELISA) kit. The GICA results were digitally displayed using a portable colloidal gold immunochromatographic test strip analyzer (HMREADER). The sensitivity, specificity, and stability of AMA1C-GICA were assessed, and this was then used to examine clinical samples, including 203 human sera, 266 cat sera, and 81 dog sera.
RESULTS
AMA1C-GICA had a detection threshold of 1:32 for T. gondii-positive serum. The GICA strips specifically detected T. gondii antibodies and exhibited no reactivity with Plasmodium vivax, Paragonimus kellicotti, Schistosoma japonicum, Clonorchis sinensis, and Schistosoma mansoni. Consequently, 15 (16.7%) positive samples were detected using the AMA1C-GICA and commercial ELISA kits for each of the assays. The receiver-operating characteristic curve showed that GICA had a relative sensitivity of 85.3% and specificity of 92%, with an area under the curve of 98%. After analyzing clinical samples using HMREADER, 1.2%-23.4% of these samples were found to be positive for T. gondii.
CONCLUSIONS
This study presents a novel assay that enables timely and efficient detection of serum antibodies against T. gondii, thereby allowing for its early clinical diagnosis. Furthermore, the integration of digital detection using HMREADER can enhance the implementation of GICA.
Topics: Mice; Animals; Dogs; Humans; Chromatography, Affinity; Sensitivity and Specificity; Immunoassay; Toxoplasmosis; Enzyme-Linked Immunosorbent Assay; Antibodies, Helminth; Gold Colloid; Toxoplasma
PubMed: 38389080
DOI: 10.1186/s13071-024-06180-1 -
Parasites & Vectors Mar 2024The elimination of schistosomiasis remains a challenging task, with current measures primarily focused on the monitoring and control of Oncomelania hupensis (O....
BACKGROUND
The elimination of schistosomiasis remains a challenging task, with current measures primarily focused on the monitoring and control of Oncomelania hupensis (O. hupensis) snail, the sole intermediate host of Schistosome japonicum. Given the emerging, re-emerging, and persistent habitats of snails, understanding their genetic diversity might be essential for their successful monitoring and control. The aims of this study were to analyze the genetic diversity of Oncomelania hupensis robertsoni (O. h. robertsoni) using microsatellite DNA markers; and validate the applicability of previously identified microsatellite loci for O. hupensis in hilly regions.
METHODS
A total of 17 populations of O. h. robertsoni from Yunnan Province in China were selected for analysis of genetic diversity using six microsatellite DNA polymorphic loci (P82, P84, T4-22, T5-11, T5-13, and T6-27).
RESULTS
The number of alleles among populations ranged from 0 to 19, with an average of 5. The average ranges of expected (He) and observed (Ho) heterozygosity within populations were 0.506 to 0.761 and 0.443 to 0.792, respectively. The average fixation index within the population ranged from - 0.801 to 0.211. The average polymorphic information content (PIC) within the population ranged from 0.411 to 0.757, appearing to be polymorphic for all loci (all PIC > 0.5), except for P28 and P48. A total of 68 loci showed significant deviations from Hardy-Weinberg equilibrium (P < 0.05), and pairwise Fst values ranged from 0.051 to 0.379. The analysis of molecular variance indicated that 88% of the variation occurred within snail populations, whereas 12% occurred among snail populations. Phylogenetic trees and principal coordinate analysis revealed two distinct clusters within the snail population, corresponding to "Yunnan North" and "Yunnan South".
CONCLUSIONS
O. h. robertsoni exhibited a relatively high level of genetic differentiation, with variation chiefly existing within snail populations. All snail in this region could be separated into two clusters. The microsatellite loci P82 and P84 might not be suitable for classification studies of O. hupensis in hilly regions. These findings provided important information for the monitoring and control of snail, and for further genetic diversity studies on snail populations.
Topics: Animals; Schistosoma japonicum; Phylogeny; China; Gastropoda; Microsatellite Repeats; DNA; Genetic Variation
PubMed: 38515113
DOI: 10.1186/s13071-024-06227-3 -
Animals : An Open Access Journal From... Feb 2024Fasciolosis is a global zoonotic parasitic disease caused by infection that is particularly harmful to cattle and sheep. A biotin-streptavidin signal amplification...
The Detection of Circulating Antigen Glutathione S-Transferase in Sheep Infected with with Double-Antibody Sandwich Signal Amplification Enzyme-Linked Immunosorbent Assay.
Fasciolosis is a global zoonotic parasitic disease caused by infection that is particularly harmful to cattle and sheep. A biotin-streptavidin signal amplification ELISA (streptavidin-ELISA/SA-ELISA) based on circulating antigens can allow for the early detection of -infected animals and is suitable for batch detection. It is considered to be a better means of detecting infection than traditional detection methods. In this study, using the serum of sheep artificially infected with , the cDNA expression library of was screened, 17 immunodominant antigen genes of were obtained, and glutathione s-transferase (GST) was selected as the candidate detection antigen. Firstly, the GST cDNA sequence was amplified from , followed by the preparation of recombinant protein GST (rFhGST). Then, monoclonal and polyclonal antibodies against rFhGST were prepared using the GST protein. Afterward, the immunolocalization of the target protein in the worm was observed via confocal microscopy, and it was found that the GST protein was localized in the uterus, intestinal tract, and body surface of . Finally, a double-antibody sandwich SA-ELISA based on the detection of circulating antigens was established. There was no cross-reaction with positive sera infected with (), (), (), or (). Forty serum and fecal samples from the same batch of sheep in Nong'an County, Changchun City, Jilin Province, China were analyzed using the established detection method and fecal detection method. The positive rate of the SA-ELISA was 17.5%, and the positive rate of the fecal detection method was 15%. The detection results of this method were 100% consistent with commercial ELISA kits. A total of 152 sheep serum samples were tested in Nong'an County, Changchun City, Jilin Province, and the positive rate was 5.92%. This study laid the foundation for the development of serological detection preparations for infection based on the detection of circulating antigens.
PubMed: 38338149
DOI: 10.3390/ani14030506 -
Scientific Reports May 2024This study intends to use the basic information and blood routine of schistosomiasis patients to establish a machine learning model for predicting liver fibrosis. We...
This study intends to use the basic information and blood routine of schistosomiasis patients to establish a machine learning model for predicting liver fibrosis. We collected medical records of Schistosoma japonicum patients admitted to a hospital in China from June 2019 to June 2022. The method was to screen out the key variables and six different machine learning algorithms were used to establish prediction models. Finally, the optimal model was compared based on AUC, specificity, sensitivity and other indicators for further modeling. The interpretation of the model was shown by using the SHAP package. A total of 1049 patients' medical records were collected, and 10 key variables were screened for modeling using lasso method, including red cell distribution width-standard deviation (RDW-SD), Mean corpuscular hemoglobin concentration (MCHC), Mean corpuscular volume (MCV), hematocrit (HCT), Red blood cells, Eosinophils, Monocytes, Lymphocytes, Neutrophils, Age. Among the 6 different machine learning algorithms, LightGBM performed the best, and its AUCs in the training set and validation set were 1 and 0.818, respectively. This study established a machine learning model for predicting liver fibrosis in patients with Schistosoma japonicum. The model could help improve the early diagnosis and provide early intervention for schistosomiasis patients with liver fibrosis.
Topics: Humans; Machine Learning; Liver Cirrhosis; Schistosomiasis japonica; Male; Female; Schistosoma japonicum; Middle Aged; Adult; Animals; China; Erythrocyte Indices; Algorithms; Aged
PubMed: 38769391
DOI: 10.1038/s41598-024-62521-1 -
Pathogens (Basel, Switzerland) Mar 2024Hepatic fibrosis is an important pathological manifestation of chronic schistosome infection. Patients with advanced schistosomiasis show varying degrees of...
Hepatic fibrosis is an important pathological manifestation of chronic schistosome infection. Patients with advanced schistosomiasis show varying degrees of abnormalities in liver fibrosis indicators and bilirubin metabolism. However, the relationship between hepatic fibrosis in schistosomiasis and dysregulated bilirubin metabolism remains unclear. In this study, we observed a positive correlation between total bilirubin levels and the levels of ALT, AST, LN, and CIV in patients with advanced schistosomiasis. Additionally, we established mouse models at different time points following infection. As the infection time increased, liver fibrosis escalated, while liver UGT1A1 consistently exhibited a low expression, indicating impaired glucuronidation of bilirubin metabolism in mice. In vitro experiments suggested that SEA may be a key inhibitor of hepatic UGT1A1 expression after schistosome infection. Furthermore, a high concentration of bilirubin activated the NF-κB signaling pathway in L-O2 cells in vitro. These findings suggested that the dysregulated glucuronidation of bilirubin caused by infection may play a significant role in schistosomiasis liver fibrosis through the NF-κB signaling pathway.
PubMed: 38668242
DOI: 10.3390/pathogens13040287 -
PLoS Pathogens Jan 2024Schistosomes are flatworm parasites that undergo a complex life cycle involving two hosts. The regulation of the parasite's developmental processes relies on both coding...
Schistosomes are flatworm parasites that undergo a complex life cycle involving two hosts. The regulation of the parasite's developmental processes relies on both coding RNAs and non-coding RNAs. However, the roles of non-coding RNAs, including long non-coding RNAs (lncRNAs) in schistosomes remain largely unexplored. Here we conduct advanced RNA sequencing on male and female S. japonicum during their pairing and reproductive development, resulting in the identification of nearly 8,000 lncRNAs. This extensive dataset enables us to construct a comprehensive co-expression network of lncRNAs and mRNAs, shedding light on their interactions during the crucial reproductive stages within the mammalian host. Importantly, we have also revealed a specific lncRNA, LNC3385, which appears to play a critical role in the survival and reproduction of the parasite. These findings not only enhance our understanding of the dynamic nature of lncRNAs during the reproductive phase of schistosomes but also highlight LNC3385 as a potential therapeutic target for combating schistosomiasis.
Topics: Animals; Male; Female; Schistosoma japonicum; RNA, Long Noncoding; RNA, Antisense; Schistosomiasis; Parasites; Mammals
PubMed: 38285715
DOI: 10.1371/journal.ppat.1011949