Screening of a Library of Recombinant <i>Schistosoma mansoni</i> Proteins With Sera From Murine and Human Controlled Infections Identifies Early Serological Markers

Crosnier, Cécile; Hokke, Cornelis H.; Protasio, Anna V.; Brandt, Cordelia; Rinaldi, Gabriel; Langenberg, Marijke C. C.; Clare, Simon; Janse, Jacqueline J.; Wilson, Shona; Berriman, Matthew; Roestenberg, Meta; Wright, Gavin J.

doi:10.1093/infdis/jiaa329

Cited by 11 publications

(10 citation statements)

References 48 publications

(48 reference statements)

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“…); (iii) using sera from experimentally infected non-endemic individuals (e.g. experimental infections in man) [51,52] or (iv) by using sera from experimentally infected animals using the original or a closely related parasite species (e.g. hookworm infections in gerbils/dogs, Schistosoma spp.…”

Section: There Is a Need For Well-characterized Biobanks For Biomarker Discoverymentioning

confidence: 99%

Identification of antigenic linear peptides in the soil-transmitted helminth and Schistosoma mansoni proteome

et al. 2021

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The scientific community identified non stool-based biomarkers as the way forward to support soil-transmitted helminth (STH; Ascaris lumbricoides, Trichuris trichiura and the hookworms Ancylostoma duodenale and Necator americanus) and schistosome (S. mansoni and S. haematobium) deworming programs. This support is needed in making the decision of whether or not to stop preventive chemotherapy intervention efforts and to ultimately transition towards a post-intervention surveillance phase. We applied a two-step micro-array approach to identify antigenic linear epitopes in the STH and S. mansoni proteomes. In a first experiment, we identified antigenic peptides by applying sera from 24 STH and/or S. mansoni infected Ethiopian children on a high-density peptide microarray containing 3.3 million peptides derived from the complete STH and S. mansoni proteomes. A second array experiment with 170,185 peptides that were recognized in the first array was designed to identify non-specific antibody reactivity by applying sera from 24 healthy individuals from Belgium (a non-endemic country). From this array testing cascade, several peptides were identified for STH but none of them appeared to be unique for one species. We therefore concluded that for STH, none of the peptides revealed to be sufficiently sensitive or species specific. For S. mansoni, some promising peptides were identified prompting future investigation. Based on these results, it is unlikely that linear epitopes would be highly useful in detecting species-specific antibody responses to STH in endemic communities. For S. mansoni, one particular peptide of the micro-exon gene 12 (MEG-12) protein deserves further research. In addition, this study emphasizes the need of well-characterized biobanks for biomarker discovery, particularly when the integration of multiple disease programs is envisioned.

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Section: There Is a Need For Well-characterized Biobanks For Biomarker Discoverymentioning

confidence: 99%

Identification of antigenic linear peptides in the soil-transmitted helminth and Schistosoma mansoni proteome

et al. 2021

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“…Crosnier and colleagues recently described the expression of 1 1 5 S . m a n s o n i p r o t e i n s a n d s c r e e n e d t h e m f o r immunoreactivity with sera from human subjects who were experimentally infected with male parasites (48). However, to express 1,000 proteins in mammalian cells would require a Herculean effort and substantial funding and definitely is not considered high-throughput.…”

Section: Discussionmentioning

confidence: 99%

Immunomics-Guided Antigen Discovery for Praziquantel-Induced Vaccination in Urogenital Human Schistosomiasis

et al. 2021

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Despite the enormous morbidity attributed to schistosomiasis, there is still no vaccine to combat the disease for the hundreds of millions of infected people. The anthelmintic drug, praziquantel, is the mainstay treatment option, although its molecular mechanism of action remains poorly defined. Praziquantel treatment damages the outermost surface of the parasite, the tegument, liberating surface antigens from dying worms that invoke a robust immune response which in some subjects results in immunologic resistance to reinfection. Herein we term this phenomenon Drug-Induced Vaccination (DIV). To identify the antigenic targets of DIV antibodies in urogenital schistosomiasis, we constructed a recombinant proteome array consisting of approximately 1,000 proteins informed by various secretome datasets including validated proteomes and bioinformatic predictions. Arrays were screened with sera from human subjects treated with praziquantel and shown 18 months later to be either reinfected (chronically infected subjects, CI) or resistant to reinfection (DIV). IgG responses to numerous antigens were significantly elevated in DIV compared to CI subjects, and indeed IgG responses to some antigens were completely undetectable in CI subjects but robustly recognized by DIV subjects. One antigen in particular, a cystatin cysteine protease inhibitor stood out as a unique target of DIV IgG, so recombinant cystatin was produced, and its vaccine efficacy assessed in a heterologous Schistosoma mansoni mouse challenge model. While there was no significant impact of vaccination with adjuvanted cystatin on adult worm numbers, highly significant reductions in liver egg burdens (45-55%, P<0.0001) and intestinal egg burdens (50-54%, P<0.0003) were achieved in mice vaccinated with cystatin in two independent trials. This study has revealed numerous antigens that are targets of DIV antibodies in urogenital schistosomiasis and offer promise as subunit vaccine targets for a drug-linked vaccination approach to controlling schistosomiasis.

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“…Consequently, there is a drive to develop a new generation of therapeutics based on schistosome genomes and their function (e.g. Berriman et al, 2009;Crosnier et al, 2020;Wang et al, 2020). Understanding the rhythms of target genes and their products will determine how an organ, or organism, will respond to a drug at a specific time of the day, and the timing of drug delivery could have a large impact on the effectiveness of target activation or inhibition (Cederroth et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Daily rhythms in the transcriptomes of the human parasite Schistosoma mansoni

Rawlinson

Reid

et al. 2021

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The consequences of the earth’s daily rotation have led to 24-hour biological rhythms in most organisms. Parasites have daily rhythms, which, when in synchrony with host rhythms, optimize their fitness. Using round-the-clock transcriptomics of male and female Schistosoma mansoni blood flukes we have discovered the first 24-hour molecular oscillations in a metazoan parasite, and gained insight into its daily rhythms. We show that expression of ∼2% of its genes followed diel cycles. Rhythmic processes, in synchrony in both sexes, included a night-time stress response and a day-time metabolic ‘rush hour’. These 24hr rhythms may be driven by host rhythms and/or generated by an intrinsic circadian clock. However, canonical core clock genes are lacking, suggesting an unusual oscillatory mechanism or loss of a functional clock. The daily rhythms in biology identified here, may promote within-host survival and between-host transmission, and are important for the development and delivery of therapeutics against schistosomiasis.

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Screening of a Library of Recombinant Schistosoma mansoni Proteins With Sera From Murine and Human Controlled Infections Identifies Early Serological Markers

Cited by 11 publications

References 48 publications

Identification of antigenic linear peptides in the soil-transmitted helminth and Schistosoma mansoni proteome

Identification of antigenic linear peptides in the soil-transmitted helminth and Schistosoma mansoni proteome

Immunomics-Guided Antigen Discovery for Praziquantel-Induced Vaccination in Urogenital Human Schistosomiasis

Daily rhythms in the transcriptomes of the human parasite Schistosoma mansoni

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