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Experimental Parasitology Nov 2015The bladder urothelium changes dramatically during Schistosoma haematobium infection (urogenital schistosomiasis). These alterations include hyperplasia, ulceration,...
INTRODUCTION AND OBJECTIVE
The bladder urothelium changes dramatically during Schistosoma haematobium infection (urogenital schistosomiasis). These alterations include hyperplasia, ulceration, dysplasia, squamous metaplasia and frank carcinogenesis. Defining the pathways underpinning these urothelial responses will contribute to a deeper understanding of how S. haematobium egg expulsion, hematuria, and bladder cancer develop in humans. The tumor suppressor gene p53 is of particular interest, given its role in many cancers, including bladder cancer generally and schistosomal bladder cancer specifically.
METHODS
Transgenic mice featuring tamoxifen-inducible Cre recombinase activity in cells expressing the urothelial-specific gene uroplakin-3a (Upk3a-GCE mice) were crossed with either TdTomato-floxed-EGFP reporter or p53-floxed mice. Mice were administered tamoxifen or vehicle control to induce excision of floxed genes. TdTomato-EGFP reporter mice were sacrificed and their bladders harvested, sectioned, and imaged by fluorescence microscopy. p53-floxed mice underwent bladder wall injection with S. haematobium eggs or vehicle controls. Three months later, mice were sacrificed and their bladders subjected to histological analysis (H&E staining).
RESULTS
We first confirmed the phenotypic fidelity of Upk3a-GCE mice by crossing them with TdTomato-floxed-EGFP reporter mice and administering tamoxifen to their progeny. As expected, these progeny switched from TdTomato to EGFP expression in their bladder urothelium. Having confirmed the phenotype of Upk3a-GCE mice, we next crossed them to p53-floxed mice. The resulting progeny were given tamoxifen or vehicle control to render them urothelial p53-haploinsufficient or -intact, respectively. Then, we injected S. haematobium eggs or control vehicle into the bladder walls of these mice. Male p53-intact, egg-injected mice exhibited similar histological changes as their p53-haploinsufficient counterparts, including urothelial hyperplasia and ulceration. In contrast, female p53-intact, egg-injected mice featured no urothelial ulceration, whereas their p53-haploinsufficient counterparts often had significant ulceration.
CONCLUSIONS
Urothelial p53 signaling indeed seems to affect urothelial homeostasis during S. haematobium infection, albeit in a sex-specific manner. Ongoing work seeks to determine whether p53 mediates associated alterations in urothelial cell cycle status and frank carcinogenesis in the setting of urogenital schistosomiasis.
Topics: Animals; Female; Genes, p53; Haploinsufficiency; Male; Mice; Mice, Inbred DBA; Ovum; Schistosoma haematobium; Schistosomiasis haematobia; Sex Factors; Urinary Bladder; Urothelium
PubMed: 26160678
DOI: 10.1016/j.exppara.2015.07.002 -
International Journal For Parasitology.... Aug 2020Human schistosomiasis is a disease which globally affects over 229 million people. Three major species affecting humans are Schistosoma mansoni, S. haematobium and S....
Human schistosomiasis is a disease which globally affects over 229 million people. Three major species affecting humans are Schistosoma mansoni, S. haematobium and S. japonicum. Previous treatment of S. mansoni includes the use of oxamniquine (OXA), a prodrug that is enzymatically activated in S. mansoni but is ineffective against S. haematobium and S. japonicum. The OXA activating enzyme was identified and crystallized, as being a S. mansoni sulfotransferase (SmSULT). S. haematobium and S. japonicum possess homologs of SmSULT (ShSULT and SjSULT) begging the question; why does oxamniquine fail to kill S. haematobium and S. japonicum adult worms? Investigation of the molecular structures of the sulfotransferases indicates that structural differences, specifically in OXA contact residues, do not abrogate OXA binding in the active sites as previously hypothesized. Data presented argue that the ability of SULTs to sulfate and thus activate OXA and its derivatives is linked to the ability of OXA to fit in the binding pocket to allow the transfer of a sulfur group.
Topics: Animals; Molecular Structure; Oxamniquine; Schistosoma; Schistosoma haematobium; Schistosoma japonicum; Schistosoma mansoni; Schistosomicides; Sulfotransferases
PubMed: 32315953
DOI: 10.1016/j.ijpddr.2020.04.001 -
International Journal of Molecular... Jul 2015The present study describes a real-time PCR approach with high resolution melting-curve (HRM) assay developed for the detection and differentiation of Schistosoma...
The present study describes a real-time PCR approach with high resolution melting-curve (HRM) assay developed for the detection and differentiation of Schistosoma mansoni and S. haematobium in fecal and urine samples collected from rural Yemen. The samples were screened by microscopy and PCR for the Schistosoma species infection. A pair of degenerate primers were designed targeting partial regions in the cytochrome oxidase subunit I (cox1) gene of S. mansoni and S. haematobium using real-time PCR-HRM assay. The overall prevalence of schistosomiasis was 31.8%; 23.8% of the participants were infected with S. haematobium and 9.3% were infected with S. mansoni. With regards to the intensity of infections, 22.1% and 77.9% of S. haematobium infections were of heavy and light intensities, respectively. Likewise, 8.1%, 40.5% and 51.4% of S. mansoni infections were of heavy, moderate and light intensities, respectively. The melting points were distinctive for S. mansoni and S. haematobium, categorized by peaks of 76.49 ± 0.25 °C and 75.43 ± 0.26 °C, respectively. HRM analysis showed high detection capability through the amplification of Schistosoma DNA with as low as 0.0001 ng/µL. Significant negative correlations were reported between the real-time PCR-HRM cycle threshold (Ct) values and microscopic egg counts for both S. mansoni in stool and S. haematobium in urine (p < 0.01). In conclusion, this closed-tube HRM protocol provides a potentially powerful screening molecular tool for the detection of S. mansoni and S. haematobium. It is a simple, rapid, accurate, and cost-effective method. Hence, this method is a good alternative approach to probe-based PCR assays.
Topics: Animals; DNA Primers; Nucleic Acid Denaturation; Real-Time Polymerase Chain Reaction; Schistosoma haematobium; Schistosoma mansoni; Schistosomiasis; Sensitivity and Specificity; Temperature
PubMed: 26193254
DOI: 10.3390/ijms160716085 -
PLoS Pathogens Feb 2021Hybridization is a fascinating evolutionary phenomenon that raises the question of how species maintain their integrity. Inter-species hybridization occurs between...
Hybridization is a fascinating evolutionary phenomenon that raises the question of how species maintain their integrity. Inter-species hybridization occurs between certain Schistosoma species that can cause important public health and veterinary issues. In particular hybrids between Schistosoma haematobium and S. bovis associated with humans and animals respectively are frequently identified in Africa. Recent genomic evidence indicates that some S. haematobium populations show signatures of genomic introgression from S. bovis. Here, we conducted a genomic comparative study and investigated the genomic relationships between S. haematobium, S. bovis and their hybrids using 19 isolates originating from a wide geographical range over Africa, including samples initially classified as S. haematobium (n = 11), S. bovis (n = 6) and S. haematobium x S. bovis hybrids (n = 2). Based on a whole genomic sequencing approach, we developed 56,181 SNPs that allowed a clear differentiation of S. bovis isolates from a genomic cluster including all S. haematobium isolates and a natural S. haematobium-bovis hybrid. All the isolates from the S. haematobium cluster except the isolate from Madagascar harbored signatures of genomic introgression from S. bovis. Isolates from Corsica, Mali and Egypt harbored the S. bovis-like Invadolysin gene, an introgressed tract that has been previously detected in some introgressed S. haematobium populations from Niger. Together our results highlight the fact that introgression from S. bovis is widespread across S. haematobium and that the observed introgression is unidirectional.
Topics: Africa; Animals; Caenorhabditis elegans; Genome; Hybridization, Genetic; Polymorphism, Single Nucleotide; Schistosoma; Schistosoma haematobium; Schistosomiasis; Species Specificity; Whole Genome Sequencing
PubMed: 33544762
DOI: 10.1371/journal.ppat.1009313 -
PLoS Neglected Tropical Diseases Dec 2021Schistosomes cause schistosomiasis, the world's second most important parasitic disease after malaria in terms of public health and social-economic impacts. A peculiar...
Schistosomes cause schistosomiasis, the world's second most important parasitic disease after malaria in terms of public health and social-economic impacts. A peculiar feature of these dioecious parasites is their ability to produce viable and fertile hybrid offspring. Originally only present in the tropics, schistosomiasis is now also endemic in southern Europe. Based on the analysis of two genetic markers the European schistosomes had previously been identified as hybrids between the livestock- and the human-infective species Schistosoma bovis and Schistosoma haematobium, respectively. Here, using PacBio long-read sequencing technology we performed genome assembly improvement and annotation of S. bovis, one of the parental species for which no satisfactory genome assembly was available. We then describe the whole genome introgression levels of the hybrid schistosomes, their morphometric parameters (eggs and adult worms) and their compatibility with two European snail strains used as vectors (Bulinus truncatus and Planorbarius metidjensis). Schistosome-snail compatibility is a key parameter for the parasites life cycle progression, and thus the capability of the parasite to establish in a given area. Our results show that this Schistosoma hybrid is strongly introgressed genetically, composed of 77% S. haematobium and 23% S. bovis origin. This genomic admixture suggests an ancient hybridization event and subsequent backcrosses with the human-specific species, S. haematobium, before its introduction in Corsica. We also show that egg morphology (commonly used as a species diagnostic) does not allow for accurate hybrid identification while genetic tests do.
Topics: Animals; Body Size; Bulinus; Chimera; Disease Vectors; Europe; Female; Genome, Helminth; Humans; Hybridization, Genetic; Male; Schistosoma; Schistosoma haematobium; Schistosomiasis; Snails
PubMed: 34941866
DOI: 10.1371/journal.pntd.0010062 -
PLoS Neglected Tropical Diseases Jan 2022Schistosomiasis remains a public health concern across sub-Saharan Africa; current control programmes rely on accurate mapping and high mass drug administration (MDA)...
Schistosomiasis remains a public health concern across sub-Saharan Africa; current control programmes rely on accurate mapping and high mass drug administration (MDA) coverage to attempt disease elimination. Inter-species hybridisation can occur between certain species, changing epidemiological dynamics within endemic regions, which has the potential to confound control interventions. The impact of hybridisation on disease dynamics is well illustrated in areas of Cameroon where urogenital schistosomiasis, primarily due to Schistosoma haematobium and hybrid infections, now predominate over intestinal schistosomiasis caused by Schistosoma guineensis. Genetic markers have shown the ability to identify hybrids, however the underlying genomic architecture of divergence and introgression between these species has yet to be established. In this study, restriction site associated DNA sequencing (RADseq) was used on archived adult worms initially identified as; Schistosoma bovis (n = 4), S. haematobium (n = 9), S. guineensis (n = 3) and S. guineensis x S. haematobium hybrids (n = 4) from Mali, Senegal, Niger, São Tomé and Cameroon. Genome-wide evidence supports the existence of S. guineensis and S. haematobium hybrid populations across Cameroon. The hybridisation of S. guineensis x S. haematobium has not been demonstrated on the island of São Tomé, where all samples showed no introgression with S. haematobium. Additionally, all S. haematobium isolates from Nigeria, Mali and Cameroon indicated signatures of genomic introgression from S. bovis. Adaptive loci across the S. haematobium group showed that voltage-gated calcium ion channels (Cav) could play a key role in the ability to increase the survivability of species, particularly in host systems. Where admixture has occurred between S. guineensis and S. haematobium, the excess introgressive influx of tegumental (outer helminth body) and antigenic genes from S. haematobium has increased the adaptive response in hybrids, leading to increased hybrid population fitness and viability.
Topics: Animals; Anthelmintics; Calcium Channels; Cameroon; Chimera; DNA, Protozoan; Humans; Male; Praziquantel; Schistosoma haematobium; Schistosomiasis haematobia; Sequence Analysis, DNA; Waterborne Diseases
PubMed: 35100291
DOI: 10.1371/journal.pntd.0010088 -
The American Journal of Tropical... Apr 2018
Topics: Africa, Eastern; Animals; Humans; Infertility; Schistosoma haematobium; Schistosomiasis haematobia
PubMed: 29405110
DOI: 10.4269/ajtmh.17-1016 -
The Korean Journal of Parasitology Jun 2015The genetic diversity of Schistosoma haematobium remains largely unstudied in comparison to that of Schistosoma mansoni. To characterize the extent of genetic diversity...
The genetic diversity of Schistosoma haematobium remains largely unstudied in comparison to that of Schistosoma mansoni. To characterize the extent of genetic diversity in S. haematobium among its definitive host (humans), we collected S. haematobium eggs from the urine of 73 infected schoolchildren at 5 primary schools in White Nile State, Sudan, and then performed a randomly amplified polymorphic DNA marker ITS2 by PCR-RFLP analysis. Among 73 S. haematobium egg-positive cases, 13 were selected based on the presence of the S. haematobium satellite markers A4 and B2 in their genomic DNA, and used for RFLP analysis. The 13 samples were subjected to an RFLP analysis of the S. haematobium ITS2 region; however, there was no variation in size among the fragments. Compared to the ITS2 sequences obtained for S. haematobium from Kenya, the nucleotide sequences of the ITS2 regions of S. haematobium from 4 areas in Sudan were consistent with those from Kenya (> 99%). In this study, we demonstrate for the first time that most of the S. haematobium population in Sudan consists of a pan-African S. haematobium genotype; however, we also report the discovery of Kenyan strain inflow into White Nile, Sudan.
Topics: Adolescent; Animals; Base Sequence; Child; DNA, Helminth; Female; Genetic Variation; Genotype; Humans; Male; Molecular Sequence Data; Ovum; Parasite Egg Count; Polymorphism, Restriction Fragment Length; Schistosoma haematobium; Schistosomiasis haematobia; Students; Sudan; Urine
PubMed: 26174820
DOI: 10.3347/kjp.2015.53.3.271 -
Schistosoma haematobium (Egyptian strain): rate of development and effect of praziquantel treatment.The Journal of Parasitology Apr 2008This study investigates the development of the Egyptian strain of Schistosoma haematobium and the resultant immunohistopathology and biochemical changes in organs...
This study investigates the development of the Egyptian strain of Schistosoma haematobium and the resultant immunohistopathology and biochemical changes in organs affected. In addition, the response of different developmental stages of S. haematobium worms to praziquantel (PZQ) was examined. Schistosoma haematobium-infected hamsters were classified into 4 groups and were treated at day 35, 55, 75, and 95 postinfection (PI), respectively. Each group was subdivided into 3 subgroups. Two of them were treated orally with PZQ (300 mg/kg or 500 mg/kg divided equally on 2 consecutive days), and the third group was left without treatment. Treated groups were killed 20 days posttreatment. Infection with S. haematobium became patent 73 days PI; tissue egg load and worm fecundity were higher at 95 days and maximal 115 days PI, with an oogram pattern comparable to that in Schistosoma mansoni infection. In the liver, small cellular granulomas were observed 75 days PI, with preponderance of CD4+ T-cell phenotypes. In the urinary bladder, only submucosal focal Brunn's-nest formation and angiogenesis without typical granulomas were observed. Ninety-five and 115 days PI, confluent granulomata with multiple eggs in the center were observed in the liver and urinary bladder, with a preponderance of CD8+ positive T cells in the liver and hyperplasia of the urinary bladder epithelium with cystitis cystica and papillae formation. One hundred percent worm eradication was recorded with the higher dose of PZQ in animals treated 75 and 95 days PI. In conclusion, in spite of the long prepatent period of the Egyptian strain of S. haematobium, sensitivity to PZQ was recorded soon after infection. Granulomata were similar to those of S. mansoni in the livers and urinary bladders, but they were confluent with multiple eggs in the centers, hyperplasia of the urinary bladder urothelium with cystitis cystica, papillae, and Brunn's-nest formation predictive of malignant changes with no hepatocyte dysplasia.
Topics: Animals; Anthelmintics; Cricetinae; Female; Immunohistochemistry; Male; Mesocricetus; Praziquantel; Schistosoma haematobium; Schistosomiasis haematobia; Time Factors
PubMed: 18564739
DOI: 10.1645/GE-1270.1 -
Infection and Immunity Jan 2019Schistosome worms infect over 200 million people worldwide. They live in the host's bloodstream and alter host immunity. Epidemiological data suggest that males and...
Schistosome worms infect over 200 million people worldwide. They live in the host's bloodstream and alter host immunity. Epidemiological data suggest that males and females have different responses to schistosome infection, but the effect of sex on systemic response is undetermined. Our objective was to characterize differences in peripheral blood transcriptional profiles in people with or without active infection and to determine whether this signature differs between males and females. mRNA was isolated using poly(A) selection and sequenced on an Illumina Hi-Seq4000 platform. Transcripts were aligned to the human hg19 reference genome and counted with the HTSeq package. Genes were compared for differential expression using DESeq2. Ingenuity Pathway Analysis (IPA) was used to identify gene networks altered in the presence of We enrolled 33 participants from villages in rural Tanzania where is endemic. After correction for multiple comparisons, we observed 383 differentially expressed genes between those with or without infection when sex was included as a covariate. Heat-mapping of the genes with >1.5-fold differences in gene expression revealed clustering by infection status. The top networks included development, cell death and survival, cell signaling, and immunologic disease pathways. We observed a distinct whole blood transcriptional profile, as well as differences in men and women, with infection. Additional studies are needed to determine the clinical effects of these divergent responses. Attention to sex-based differences should be included in studies of human schistosome infection.
Topics: Adolescent; Adult; Animals; Blood Cells; Female; Gene Expression Profiling; Gene Regulatory Networks; Host-Pathogen Interactions; Humans; Male; Middle Aged; Schistosoma haematobium; Schistosomiasis haematobia; Sequence Analysis, RNA; Sex Factors; Tanzania; Young Adult
PubMed: 30323023
DOI: 10.1128/IAI.00291-18