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dc.contributor.authorShiels, Jenna
dc.contributor.authorCwiklinski, Krystyna
dc.contributor.authorAlvarado, Raquel
dc.contributor.authorThivierge, Karine
dc.contributor.authorCotton, Sophie
dc.contributor.authorGonzales Santana, Bibiana
dc.contributor.authorTo, Joyce
dc.contributor.authorDonnelly, Sheila
dc.contributor.authorTaggart, Clifford C.
dc.contributor.authorWeldon, Sinead
dc.contributor.authorDalton, John P.
dc.date.accessioned2020-07-28T09:32:59Z
dc.date.available2020-07-28T09:32:59Z
dc.date.issued2020-07-09
dc.identifier.citationShiels J, Cwiklinski K, Alvarado R, Thivierge K, Cotton S, Gonzales Santana B, et al. (2020) Schistosoma mansoni immunomodulatory molecule Sm16/SPO-1/SmSLP is a member of the trematode-specific helminth defence molecules (HDMs). PLoS Negl Trop Dis 14(7): e0008470. https://doi.org/10.1371/journal.pntd.0008470en_IE
dc.identifier.issn1935-2735
dc.identifier.urihttp://hdl.handle.net/10379/16105
dc.description.abstractSm16, also known as SPO-1 and SmSLP, is a low molecular weight protein (~16kDa) secreted by the digenean trematode parasite Schistosoma mansoni, one of the main causative agents of human schistosomiasis. The molecule is secreted from the acetabular gland of the cercariae during skin invasion and is believed to perform an immune-suppressive function to protect the invading parasite from innate immune cell attack. We show that Sm16 homologues of the Schistosomatoidea family are phylogenetically related to the helminth defence molecule (HDM) family of immunomodulatory peptides first described in Fasciola hepatica. Interrogation of 69 helminths genomes demonstrates that HDMs are exclusive to trematode species. Structural analyses of Sm16 shows that it consists predominantly of an amphipathic alpha-helix, much like other HDMs. In S. mansoni, Sm16 is highly expressed in the cercariae and eggs but not in adult worms, suggesting that the molecule is of importance not only during skin invasion but also in the pro-inflammatory response to eggs in the liver tissues. Recombinant Sm16 and a synthetic form, Sm16 (34-117), bind to macrophages and are internalised into the endosomal/lysosomal system. Sm16 (34-117) elicited a weak pro-inflammatory response in macrophages in vitro but also suppressed the production of bacterial lipopolysaccharide (LPS)-induced inflammatory cytokines. Evaluation of the transcriptome of human macrophages treated with a synthetic Sm16 (34-117) demonstrates that the peptide exerts significant immunomodulatory effects alone, as well as in the presence of LPS. Pathways most significantly influenced by Sm16 (34-117) were those involving transcription factors peroxisome proliferator-activated receptor (PPAR) and liver X receptors/retinoid X receptor (LXR/RXR) which are intricately involved in regulating the cellular metabolism of macrophages (fatty acid, cholesterol and glucose homeostasis) and are central to inflammatory responses. These results offer new insights into the structure and function of a well-known immunomodulatory molecule, Sm16, and places it within a wider family of trematode-specific small molecule HDM immune-modulators with immuno-biotherapeutic possibilities.en_IE
dc.description.sponsorshipJS was supported by a fellowship provided by the Department for the Economy through Queen’s University Belfast, Northern Ireland, UK. KT, SC, BGS and JPD were supported by a Canadian Institute of Health Research (CIHR) Chair (Tier 1) in Infectious Diseases awarded to JPD (https://cihr-irsc.gc.ca/e/193.html). KC and JPD were funded by the Science Foundation Ireland (SFI, Republic of Ireland) Research Professorship grant 17/RP/5368 (https://www.sfi.ie/). RA, JT and SD were supported by an NHMRC project grant APP1142006 (https://www.nhmrc.gov.au/). CCT and SW are supported by the Medical Research Council, UK (https://mrc.ukri.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en_IE
dc.formatapplication/pdfen_IE
dc.language.isoenen_IE
dc.publisherPublic Library of Scienceen_IE
dc.relation.ispartofPlos Neglected Tropical Diseasesen
dc.subjectSchistosoma mansonien_IE
dc.subjectimmunomodulatory molecule Sm16/SPO-1/SmSLPen_IE
dc.subjecttrematode-specific helminth defence molecules (HDMs)en_IE
dc.titleSchistosoma mansoni immunomodulatory molecule Sm16/SPO-1/SmSLP is a member of the trematode-specific helminth defence molecules (HDMs)en_IE
dc.typeArticleen_IE
dc.date.updated2020-07-27T12:39:13Z
dc.identifier.doi10.1371/journal.pntd.0008470
dc.local.publishedsourcehttps://doi.org/10.1371/journal.pntd.0008470en_IE
dc.description.peer-reviewedpeer-reviewed
dc.contributor.funderScience Foundation Irelanden_IE
dc.internal.rssid22009436
dc.local.contactKrystyna Cwiklinski. Email: krystyna.cwiklinski@nuigalway.ie
dc.local.copyrightcheckedYes
dc.local.versionACCEPTED
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