Identification and characterisation of the tegument-expressed aldehyde dehydrogenase SmALDH_312 of Schistosoma mansoni, a target of disulfiram

Beutler, Mandy; Harnischfeger, Julie; Weber, Michael; Hahnel, Steffen; Quack, Thomas; Blohm, Ariane; Ueberall, Monique E.; Lochnit, Günter; Rennar, Georg A.; Gallinger, Tom L.; Houhou, Hicham; Rahlfs, Stefan; Falcone, Franco H.; Becker, Katja; Schlitzer, Martin; Haeberlein, Simone; Czermak, Peter; Salzig, Denise; Grevelding, Christoph G.

doi:10.1016/j.ejmech.2023.115179

Cited by 6 publications

(5 citation statements)

References 102 publications

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“… 36 Transcript levels of the gene encoding tegument aldehyde dehydrogenase, SmALDH_312, differed between male and females Liberian strain S. mansoni worms. 37 Our findings are thus in accord with the considerable differences in protein content and activity between male and females recorded in S. japonicum , S. mekongi , and S. mansoni ( 36 − 42 ) and additionally reveal the distinct properties of the worm surface tegument and body. High surface membrane nSMase activity could be deleterious, as it is readily increased after exposure to the high levels of unsaturated fatty acids in the portal and mesenteric circulation.…”

Section: Discussionsupporting

confidence: 88%

“…Transcript levels of the gene encoding tegument aldehyde dehydrogenase, SmALDH_312, differed between male and females Liberian strain S. mansoni worms . Our findings are thus in accord with the considerable differences in protein content and activity between male and females recorded in S.…”

Section: Discussionmentioning

confidence: 96%

“…mekongi, and S. mansoni − and additionally reveal the distinct properties of the worm surface tegument and body. High surface membrane nSMase activity could be deleterious, as it is readily increased after exposure to the high levels of unsaturated fatty acids in the portal and mesenteric circulation. ,,,− Excessive nSMase activation will lead to SM hydrolysis, surface membrane disintegration, and worm death.…”

Section: Discussionmentioning

confidence: 96%

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Mechanisms of Arachidonic Acid In Vitro Schistosomicidal Potential

Tallima,

Mahmoud

2024

ACS Omega

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Arachidonic acid (ARA) was shown to possess safe and effective schistosomicidal impact on larval and adult Schistosoma mansoni and Schistosoma hematobium in vitro and in vivo in laboratory rodents and in children residing in low and high endemicity regions. We herein examine mechanisms underlying ARA schistosomicidal potential over two experiments, using in each pool a minimum of 50 adult male, female, or mixed-sex freshly recovered, ex vivo S. mansoni. Worms incubated in fetal calf serum-free medium were exposed to 0 or 10 mM ARA for 1 h at 37 °C and immediately processed for preparation of surface membrane and whole worm body homogenate extracts. Mixed-sex worms were additionally used for evaluating the impact of ARA exposure on the visualization of outer membrane cholesterol, sphingomyelin (SM), and ceramide in immunofluorescence assays. Following assessment of protein content, extracts of intact and ARA-treated worms were examined and compared for SM content, neutral sphingomyelinase activity, reactive oxygen species levels, and caspase 3/7 activity. Arachidonic acid principally led to perturbation of the organization, integrity, and SM content of the outer membrane of male and female worms and additionally impacted female parasites via stimulating neutral sphingomyelinase activity and oxidative stress. Arachidonic powerful action on female worms combined with its previously documented ovocidal activities supports its use as safe and effective therapy against schistosomiasis, provided implementation of the sorely needed and long waited-for chemical synthesis.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 96%

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Mechanisms of Arachidonic Acid In Vitro Schistosomicidal Potential

Tallima,

Mahmoud

2024

ACS Omega

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“…Cloned sequences were confirmed by Sanger sequencing (Microsynth Seqlab, Germany) (sequencing primer: 5’-TTCTGCGGACTGGCTTTCTAC-3’ 84 ) and WormBase ParaSite BLAST (see Table S6 for results). Templates for in vitro transcription were generated by PCR amplification (Q5 High-Fidelity DNA Polymerase, New England Biolabs) from plasmids using a T7 extended primer (5’-CCTAATACGACTCACTATAGGGAG-3’ 85 ). In vitro transcription was finally performed using T3 or SP6 RNA polymerases (Roche, Germany) with the addition of Digoxigenin-11-UTP (Roche).…”

Section: Methodsmentioning

confidence: 99%

Spatial transcriptomics of a parasitic flatworm provides a molecular map of vaccine candidates, drug targets and drug resistance genes

Gramberg,

Puckelwaldt,

Schmitt

et al. 2023

Preprint

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The spatial organization of gene expression dictates tissue functions in multicellular parasites. Here, we present the first spatial transcriptome of a parasitic flatworm, the common liver flukeFasciola hepatica.We identified gene expression profiles and marker genes for eight distinct tissues and validated the latter byin situhybridization. To demonstrate the power of our spatial atlas, we focused on genes with substantial medical importance, including vaccine candidates (Ly6 proteins), drug targets (β-tubulins, protein kinases) and drug resistance genes (glutathione S-transferases, ABC transporters). Several of these genes exhibited unique expression patterns, indicating tissue-specific biological functions. Notably, the prioritization of tegumental protein kinases identified a PKCβ, for which small-molecule targeting caused parasite death. Our comprehensive gene expression map provides unprecedented molecular insights into the organ systems of this complex parasitic organism, serving as a valuable tool for both basic and applied research.

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“…The majority of these drugs/formulations are not (yet?) approved for human use and have not been examined in vivo; the conclusions concerning their possible use are mostly based on in vitro effects in worm membrane and tegumental integrity (e.g., Beutler et al 2023 ). Of these publications, a few deal with the potential use of ivermectin for treating schistosomiasis (e.g., Keiser and Utzinger 2012 ; Moreira et al 2022 ; Siddiqui et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Considering ivermectin for treatment of schistosomiasis

Golenser,

Birman,

Gold

2024

Parasitol Res

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Because of recent reports of praziquantel resistance in schistosome infections, there have been suggestions to employ ivermectin as a possible alternative, especially as its chemical composition is different from that of praziquantel, so cross-resistance is not expected. In order to ascertain possible damage and elimination of worms, we used ivermectin by oral gavage in infected mice, at a high dose (30.1 mg/kg, bordering toxicity). We also tested the efficacy of the drug at various times postinfection (PI), to check on possible effect on young and mature stages of the parasites. Thus, we treated mice on days 21 and 22 or on days 41 and 42 and even on days 21, 22, 41, and 42 PI. None of the treatment regimens resulted in cure rates or signs of lessened pathology in the mice. We also compared the effect of ivermectin to that of artemisone, an artemisinin derivative which had served us in the past as an effective anti-schistosome drug, and there was a stark difference in the artemisone’s efficacy compared to that of ivermectin; while ivermectin was not effective, artemisone eliminated most of the worms, prevented egg production and granulomatous inflammatory response. We assume that the reported lack of activity of ivermectin, in comparison with praziquantel and artemisinins, originates from the difference in their mode of action. In wake of our results, we suggest that ivermectin is not a suitable drug for treatment of schistosomiasis.

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Identification and characterisation of the tegument-expressed aldehyde dehydrogenase SmALDH_312 of Schistosoma mansoni, a target of disulfiram

Cited by 6 publications

References 102 publications

Mechanisms of Arachidonic Acid In Vitro Schistosomicidal Potential

Mechanisms of Arachidonic Acid In Vitro Schistosomicidal Potential

Spatial transcriptomics of a parasitic flatworm provides a molecular map of vaccine candidates, drug targets and drug resistance genes

Considering ivermectin for treatment of schistosomiasis

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