BACKGROUND: Schistosoma mansoni was introduced from Africa to the Americas during the transatlantic slave trade and remains a major public health problem in parts of South America and the Caribbean. This study presents a comprehensive comparative analysis of three S. mansoni strains with different geographical origins-from Liberia, Belo Horizonte and Puerto Rico. We demonstrated significant variation in virulence and host-parasite interactions. METHODS: We investigated the phenotypic characteristics of the parasite and its eggs, as well as the immunopathologic effects on laboratory mouse organ systems. RESULTS: Our results show significant differences in worm morphology, worm burden, egg size, and pathologic organ changes between these strains. The Puerto Rican strain showed the highest virulence, as evidenced by marked liver and spleen changes and advanced liver fibrosis indicated by increased collagen content. In contrast, the strains from Liberia and Belo Horizonte had a less pathogenic profile with less liver fibrosis. We found further variations in granuloma formation, cytokine expression and T-cell dynamics, indicating different immune responses. CONCLUSION: Our study emphasizes the importance of considering intra-specific variations of S. mansoni for the development of targeted therapies and public health strategies. The different virulence patterns, host immune responses and organ pathologies observed in these strains provide important insights for future research and could inform region-specific interventions for schistosomiasis control.
- MeSH
- cytokiny metabolismus MeSH
- interakce hostitele a parazita MeSH
- játra * parazitologie patologie MeSH
- myši MeSH
- Schistosoma mansoni * patogenita genetika imunologie MeSH
- schistosomiasis mansoni * parazitologie imunologie patologie MeSH
- slezina parazitologie patologie imunologie MeSH
- virulence MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Libérie MeSH
- Portoriko MeSH
Skin uses interdependent cellular networks for barrier integrity and host immunity, but most underlying mechanisms remain obscure. Herein, we demonstrate that the human parasitic helminth Schistosoma mansoni inhibited pruritus evoked by itch-sensing afferents bearing the Mas-related G-protein-coupled receptor A3 (MrgprA3) in mice. MrgprA3 neurons controlled interleukin (IL)-17+ γδ T cell expansion, epidermal hyperplasia and host resistance against S. mansoni through shaping cytokine expression in cutaneous antigen-presenting cells. MrgprA3 neuron activation downregulated IL-33 but induced IL-1β and tumor necrosis factor in macrophages and type 2 conventional dendritic cells partially through the neuropeptide calcitonin gene-related peptide. Macrophages exposed to MrgprA3-derived secretions or bearing cell-intrinsic IL-33 deletion showed increased chromatin accessibility at multiple inflammatory cytokine loci, promoting IL-17/IL-23-dependent changes to the epidermis and anti-helminth resistance. This study reveals a previously unrecognized intercellular communication mechanism wherein itch-inducing MrgprA3 neurons initiate host immunity against skin-invasive parasites by directing cytokine expression patterns in myeloid antigen-presenting cell subsets.
- MeSH
- dendritické buňky imunologie MeSH
- interleukin 33 * metabolismus imunologie MeSH
- kůže imunologie parazitologie MeSH
- lidé MeSH
- makrofágy imunologie metabolismus MeSH
- myeloidní buňky imunologie metabolismus MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- neurony imunologie metabolismus MeSH
- pruritus imunologie MeSH
- receptory spřažené s G-proteiny * metabolismus imunologie genetika MeSH
- Schistosoma mansoni * imunologie MeSH
- schistosomiasis mansoni * imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND AND AIMS: Schistosoma mansoni infection is one of the worldwide leading causes of liver fibrosis and portal hypertension. The objective of this study was to evaluate whether polyhydroxylated bile acids (BAs), known to protect mice from the development of acquired cholestatic liver injury, counteract S. mansoni-induced inflammation and fibrosis. METHODS: Adult FVB/N wild type (WT) and Abcb11/Bsep-/- mice were infected with either 25 or 50 S. mansoni cercariae. Eight weeks post infection, effects on liver histology, serum biochemistry, gene expression profile of proinflammatory cytokines and fibrotic markers, hepatic hydroxyproline content and FACS analysis were performed. RESULTS: Bsep-/- mice infected with S. mansoni showed significantly less hepatic inflammation and tendentially less fibrosis compared to infected WT mice. Despite elevated alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels in infected Bsep-/- mice, inflammatory cells such as M2 macrophages and Mac-2/galectin-3+ cells were reduced in these animals. Accordingly, mRNA-expression levels of anti-inflammatory cytokines (IL-4 and IL-13) were increased in Bsep-/- mice upon infection. Furthermore, infected Bsep-/- mice exhibited decreased hepatic egg load and parasite fecundity, consequently affecting the worm reproduction rate. This outcome could arise from elevated serum BA levels and lower blood pH in Bsep-/- mice. CONCLUSIONS: The loss of Bsep and the resulting changes in bile acid composition and blood pH are associated with the reduction of parasite fecundity, thus attenuating the development of S. mansoni-induced hepatic inflammation and fibrosis.
- MeSH
- cytokiny metabolismus MeSH
- fertilita MeSH
- jaterní cirhóza prevence a kontrola etiologie MeSH
- játra patologie MeSH
- myši MeSH
- paraziti * MeSH
- Schistosoma mansoni MeSH
- schistosomiasis mansoni * komplikace MeSH
- zánět patologie MeSH
- žlučové kyseliny a soli metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Serine proteases are important virulence factors for many pathogens. Recently, we discovered a group of trypsin-like serine proteases with domain organization unique to flatworm parasites and containing a thrombospondin type 1 repeat (TSR-1). These proteases are recognized as antigens during host infection and may prove useful as anthelminthic vaccines, however their molecular characteristics are under-studied. Here, we characterize the structural and proteolytic attributes of serine protease 2 (SmSP2) from Schistosoma mansoni, one of the major species responsible for the tropical infectious disease, schistosomiasis. METHODOLOGY/PRINCIPAL FINDINGS: SmSP2 comprises three domains: a histidine stretch, TSR-1 and a serine protease domain. The cleavage specificity of recombinant SmSP2 was determined using positional scanning and multiplex combinatorial libraries and the determinants of specificity were identified with 3D homology models, demonstrating a trypsin-like endopeptidase mode of action. SmSP2 displayed restricted proteolysis on protein substrates. It activated tissue plasminogen activator and plasminogen as key components of the fibrinolytic system, and released the vasoregulatory peptide, kinin, from kininogen. SmSP2 was detected in the surface tegument, esophageal glands and reproductive organs of the adult parasite by immunofluorescence microscopy, and in the excretory/secretory products by immunoblotting. CONCLUSIONS/SIGNIFICANCE: The data suggest that SmSP2 is secreted, functions at the host-parasite interface and contributes to the survival of the parasite by manipulating host vasodilatation and fibrinolysis. SmSP2 may be, therefore, a potential target for anti-schistosomal therapy.
- MeSH
- fibrinolýza účinky léků MeSH
- hemokoagulace účinky léků MeSH
- hemostatika antagonisté a inhibitory MeSH
- krevní tlak účinky léků MeSH
- molekulární modely MeSH
- plazminogen účinky léků MeSH
- proteinové domény MeSH
- proteiny červů chemie genetika farmakologie MeSH
- proteolýza účinky léků MeSH
- rekombinantní proteiny MeSH
- Schistosoma mansoni enzymologie MeSH
- schistosomiasis mansoni parazitologie MeSH
- sekvence aminokyselin MeSH
- serinové endopeptidasy chemie genetika farmakologie MeSH
- tkáňový aktivátor plazminogenu účinky léků MeSH
- vazodilatace účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Schistosomiasis is one of a number of chronic helminth diseases of poverty that severely impact personal and societal well-being and productivity. Peptidases (proteases) are vital to successful parasitism, and can modulate host physiology and immunology. Interference of peptidase action by specific drugs or vaccines can be therapeutically beneficial. To date, research on peptidases in the schistosome parasite has focused on either the functional characterization of individual peptidases or their annotation as part of global genome or transcriptome studies. We were interested in functionally characterizing the complexity of peptidase activity operating at the host-parasite interface, therefore the excretory-secretory products of key developmental stages of Schistosoma mansoni that parasitize the human were examined. Using class specific peptidase inhibitors in combination with a multiplex substrate profiling assay, a number of unique activities derived from endo- and exo-peptidases were revealed in the excretory-secretory products of schistosomula (larval migratory worms), adults and eggs. The data highlight the complexity of the functional degradome for each developmental stage of this parasite and facilitate further enquiry to establish peptidase identity, physiological and immunological function, and utility as drug or vaccine candidates.
- MeSH
- interakce hostitele a patogenu MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- ovum metabolismus MeSH
- proteasy metabolismus sekrece MeSH
- proteiny červů metabolismus sekrece MeSH
- proteolýza MeSH
- Schistosoma mansoni růst a vývoj metabolismus fyziologie MeSH
- schistosomiasis mansoni parazitologie MeSH
- sekvence aminokyselin MeSH
- stadia vývoje MeSH
- substrátová specifita MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Schistosomiasis affects millions of people across Africa. We detected eggs of Schistosoma mansoni in western lowland gorilla and central chimpanzee fecal samples in Loango National Park, Gabon. We analyzed nuclear and mitochondrial DNA, namely internal transcribed spacer and cytochrome c oxidase subunit 1 fragments, and the resulting maximum likelihood phylogenetic analyses and haplotype network of the ITS and COI, respectively, showed that the samples from gorillas and chimpanzees clustered clearly within the S. mansoni clade. This is the first confirmed record of S. mansoni from Gabon, which urges surveillance in the area and prompts questions regarding the extent of zoonotic transmission and the clinical impact.
- MeSH
- feces parazitologie MeSH
- fylogeneze MeSH
- Gorilla gorilla parazitologie MeSH
- haplotypy MeSH
- intergenová DNA genetika MeSH
- mitochondriální DNA genetika MeSH
- objevující se infekční nemoci epidemiologie veterinární MeSH
- opomíjené nemoci epidemiologie veterinární MeSH
- Pan troglodytes parazitologie MeSH
- podjednotky proteinů MeSH
- respirační komplex IV genetika MeSH
- Schistosoma mansoni genetika izolace a purifikace MeSH
- schistosomiasis mansoni epidemiologie veterinární MeSH
- sekvenční analýza DNA MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Gabon epidemiologie MeSH
Schistosomiasis caused by a parasitic blood fluke of the genus Schistosoma afflicts over 200 million people worldwide. Schistosoma mansoni cathepsin B1 (SmCB1) is a gut-associated peptidase that digests host blood proteins as a source of nutrients. It is under investigation as a drug target. To further this goal, we report three crystal structures of SmCB1 complexed with peptidomimetic inhibitors as follows: the epoxide CA074 at 1.3 Å resolution and the vinyl sulfones K11017 and K11777 at 1.8 and 2.5 Å resolutions, respectively. Interactions of the inhibitors with the subsites of the active-site cleft were evaluated by quantum chemical calculations. These data and inhibition profiling with a panel of vinyl sulfone derivatives identify key binding interactions and provide insight into the specificity of SmCB1 inhibition. Furthermore, hydrolysis profiling of SmCB1 using synthetic peptides and the natural substrate hemoglobin revealed that carboxydipeptidase activity predominates over endopeptidolysis, thereby demonstrating the contribution of the occluding loop that restricts access to the active-site cleft. Critically, the severity of phenotypes induced in the parasite by vinyl sulfone inhibitors correlated with enzyme inhibition, providing support that SmCB1 is a valuable drug target. The present structure and inhibitor interaction data provide a footing for the rational design of anti-schistosomal inhibitors.
- MeSH
- hemoglobiny chemie MeSH
- hydrolýza účinky léků MeSH
- inhibitory proteas chemie MeSH
- kathepsin D antagonisté a inhibitory chemie genetika MeSH
- krystalografie rentgenová MeSH
- lékové transportní systémy MeSH
- lidé MeSH
- peptidomimetika chemie MeSH
- peptidy chemie MeSH
- proteiny červů antagonisté a inhibitory chemie genetika MeSH
- Schistosoma mansoni enzymologie genetika MeSH
- schistosomiasis mansoni farmakoterapie enzymologie genetika MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Several authors have reported schistosomiasis caused by Schistosoma haematobium in the female genital tract of patients in endemic areas. This work describes tubal schistosomiasis by Schistosoma mansoni in a Brazilian woman submitted to hysterectomy for uterine myomatosis and metrorrhagia. Macroscopy evidenced hydrosalpinx of the left tube and multiple Schistosoma mansoni eggs were identified by anatomopathological examination. This article illustrates a rare form of schistosomiasis as the cause of tubal damage.
- MeSH
- dospělí MeSH
- farmakoterapie metody využití MeSH
- hysterektomie metody využití MeSH
- lidé MeSH
- metroragie chirurgie MeSH
- mikroskopie metody využití MeSH
- myom chirurgie MeSH
- nemoci vejcovodů diagnóza etiologie parazitologie MeSH
- oxamnichin aplikace a dávkování terapeutické užití MeSH
- praziquantel aplikace a dávkování terapeutické užití MeSH
- schistosomiasis mansoni diagnóza etiologie parazitologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- Geografické názvy
- Brazílie MeSH
- MeSH
- asijská schistosomóza epidemiologie komplikace prevence a kontrola MeSH
- lidé MeSH
- parazitární nemoci epidemiologie komplikace prevence a kontrola MeSH
- protozoální vakcíny * imunologie MeSH
- Schistosoma * růst a vývoj MeSH
- schistosomiasis haematobia epidemiologie komplikace prevence a kontrola MeSH
- schistosomiasis mansoni epidemiologie komplikace prevence a kontrola MeSH
- schistosomóza * epidemiologie komplikace prevence a kontrola MeSH
- vakcinace MeSH
- výzkum MeSH
- Check Tag
- lidé MeSH
