Human serum activates the tegument of female schistosomes and supports recovery from Praziquantel

Winkelmann, Franziska; Frank, Marcus; Rabes, Anne; Koslowski, Nicole; Schulz, Cindy; Bischofsberger, Miriam; Reisinger, Emil C.; Sombetzki, Martina

doi:10.1007/s00436-020-06968-x

Cited by 8 publications

(6 citation statements)

References 63 publications

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“…The ensuing PZQ-induced tegument vacuolation and blebbing exposes the worm surface antigens, previously concealed in the intact live parasite to host's immune system (Figure 1) (162). In vivo studies show extensive structural changes in the tegument, subtegumental and gastro-dermal musculature, causing leakage of tegumental cytoplasm from live worm in the first 15 min of PZQ treatment (163). Rodent studies have shown that PZQinduced tegument disruption leads to exposure of a previously concealed native GST enzyme 90 minutes post PZQ treatment (164).…”

Section: Pzq Co-administrationmentioning

confidence: 96%

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings

et al. 2021

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Despite mass drug administration programmes with praziquantel, the prevalence of schistosomiasis remains high. A vaccine is urgently needed to control transmission of this debilitating disease. As some promising schistosomiasis vaccine candidates are moving through pre-clinical and clinical testing, we review the immunological challenges that these vaccine candidates may encounter in transitioning through the clinical trial phases in endemic settings. Prior exposure of the target population to schistosomes and other infections may impact vaccine response and efficacy and therefore requires considerable attention. Schistosomes are known for their potential to induce T-reg/IL-10 mediated immune suppression in populations which are chronically infected. Moreover, endemicity of schistosomiasis is focal whereby target and trial populations may exhibit several degrees of prior exposure as well as in utero exposure which may increase heterogeneity of vaccine responses. The age dependent distribution of exposure and development of acquired immunity, and general differences in the baseline immunological profile, adds to the complexity of selecting suitable trial populations. Similarly, prior or concurrent infections with other parasitic helminths, viral and bacterial infections, may alter immunological responses. Consequently, treatment of co-infections may benefit the immunogenicity of vaccines and may be considered despite logistical challenges. On the other hand, viral infections leave a life-long immunological imprint on the human host. Screening for serostatus may be needed to facilitate interpretation of vaccine responses. Co-delivery of schistosome vaccines with PZQ is attractive from a perspective of implementation but may complicate the immunogenicity of schistosomiasis vaccines. Several studies have reported PZQ treatment to induce both transient and long-term immuno-modulatory effects as a result of tegument destruction, worm killing and subsequent exposure of worm antigens to the host immune system. These in turn may augment or antagonize vaccine immunogenicity. Understanding the complex immunological interactions between vaccine, co-infections or prior exposure is essential in early stages of clinical development to facilitate phase 3 clinical trial design and implementation policies. Besides well-designed studies in different target populations using schistosome candidate vaccines or other vaccines as models, controlled human infections could also help identify markers of immune protection in populations with different disease and immunological backgrounds.

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Section: Pzq Co-administrationmentioning

confidence: 96%

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings

et al. 2021

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“…Further work is required to unravel the modulatory effects of PZQ on CaMKII and its relevant functional partners. Such investigations could include separate sex experiments with adult worms of different ages, with and without human serum, because males are more susceptible than females and worm susceptibility changes with age 16 , and because while the tegument damage occurs in both sexes, human serum seems to mitigate the effects of PZQ in females 48 . Studies with PZQ enantiomers and anti-schistosome PZQ derivatives 49 would also highlight further the importance CaMKII in schistosome PZQ response mechanisms.…”

Section: Discussionmentioning

confidence: 99%

CaMKII regulates neuromuscular activity and survival of the human blood fluke Schistosoma mansoni

Hirst

Lawton

Walker

2022

Sci Rep

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Calcium/calmodulin dependant protein kinase II (CaMKII), an important transducer of Ca2+ signals, orchestrates multiple cellular functions in animals. Here we investigated the importance of CaMKII to Schistosoma mansoni, a blood parasite that causes human schistosomiasis. We demonstrate that phosphorylated (activated) CaMKII is present in cercariae, schistosomula and adult worms, and show that striking activation occurs in the nervous tissue of these parasite life-stages; CaMKII was also activated in the tegument and muscles of adult worms and the vitellaria of females. Exposure of worms to the anti-schistosomal drug praziquantel (PZQ) induced significant CaMKII activation and depletion of CaMKII protein/activation in adult worms resulted in hypokinesia, reduced vitality and death. At medium confidence (global score ≥ 0.40), S. mansoni CaMKII was predicted to interact with 51 proteins, with many containing CaMKII phosphorylation sites and nine mapped to phosphoproteome data including sites within a ryanodine receptor. The CaMKII network was functionally enriched with mitogen-activated protein kinase, Wnt, and notch pathways, and ion-transport and voltage-dependent channel protein domains. Collectively, these data highlight the intricacies of CaMKII signalling in S. mansoni, show CaMKII to be an active player in the PZQ-mediated response of schistosomes and highlight CaMKII as a possible target for the development of novel anti-schistosome therapeutics.

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“…Images of reproductive organs (testes, ovaries) were captured and analysed by ImageJ (v. 1.53). To analyse the surface tegument, the parasites were processed for scanning electron microscopy as described before 22 and the standardized medial posterior part of parasites was examined.…”

Section: Methodsmentioning

confidence: 99%

Bsep/Abcb11 knockout ameliorates Schistosoma mansoni liver pathology by reducing parasite fecundity

Macháček,

Fuchs,

Winkelmann

et al. 2023

Liver International

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Background and AimsSchistosoma 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.MethodsAdult 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.ResultsBsep−/− 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.ConclusionsThe 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.

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Human serum activates the tegument of female schistosomes and supports recovery from Praziquantel

Cited by 8 publications

References 63 publications

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings

CaMKII regulates neuromuscular activity and survival of the human blood fluke Schistosoma mansoni

Bsep/Abcb11 knockout ameliorates Schistosoma mansoni liver pathology by reducing parasite fecundity

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