Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure.
Control of the neglected tropical disease schistosomiasis relies almost entirely on praziquantel (PZQ) monotherapy. How PZQ clears parasite infections remains poorly understood. Many studies have examined the effects of PZQ on worms cultured in vitro, observing outcomes such as muscle contraction. H...
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ftdoajarticles:oai:doaj.org/article:a01e036cacf64e4f84fcde1800ac27ae 2023-05-15T15:14:50+02:00 Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure. Paul McCusker Claudia M Rohr John D Chan 2021-03-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0009200 https://doaj.org/article/a01e036cacf64e4f84fcde1800ac27ae EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0009200 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009200 https://doaj.org/article/a01e036cacf64e4f84fcde1800ac27ae PLoS Neglected Tropical Diseases, Vol 15, Iss 3, p e0009200 (2021) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2021 ftdoajarticles https://doi.org/10.1371/journal.pntd.0009200 2022-12-31T02:25:15Z Control of the neglected tropical disease schistosomiasis relies almost entirely on praziquantel (PZQ) monotherapy. How PZQ clears parasite infections remains poorly understood. Many studies have examined the effects of PZQ on worms cultured in vitro, observing outcomes such as muscle contraction. However, conditions worms are exposed to in vivo may vary considerably from in vitro experiments given the short half-life of PZQ and the importance of host immune system engagement for drug efficacy in animal models. Here, we investigated the effects of in vivo PZQ exposure on Schistosoma mansoni. Measurement of pro-apoptotic caspase activation revealed that worm death occurs only after parasites shift from the mesenteric vasculature to the liver, peaking 24 hours after drug treatment. This indicates that PZQ is not directly schistocidal, since PZQ's half-life is ~2 hours in humans and ~30 minutes in mice, and focuses attention on parasite interactions with the host immune system following the shift of worms to the liver. RNA-Seq of worms harvested from mouse livers following sub-lethal PZQ treatment revealed drug-evoked changes in the expression of putative immunomodulatory and anticoagulant gene products. Several of these gene products localized to the schistosome esophagus and may be secreted into the host circulation. These include several Kunitz-type protease inhibitors, which are also found in the secretomes of other blood feeding animals. These transcriptional changes may reflect mechanisms of parasite immune-evasion in response to chemotherapy, given the role of complement-mediated attack and the host innate/humoral immune response in parasite elimination. One of these isoforms, SmKI-1, has been shown to exhibit immunomodulatory and anti-coagulant properties. These data provide insight into the effect of in vivo PZQ exposure on S. mansoni, and the transcriptional response of parasites to the stress of chemotherapy. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 15 3 e0009200 |
institution |
Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Paul McCusker Claudia M Rohr John D Chan Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Control of the neglected tropical disease schistosomiasis relies almost entirely on praziquantel (PZQ) monotherapy. How PZQ clears parasite infections remains poorly understood. Many studies have examined the effects of PZQ on worms cultured in vitro, observing outcomes such as muscle contraction. However, conditions worms are exposed to in vivo may vary considerably from in vitro experiments given the short half-life of PZQ and the importance of host immune system engagement for drug efficacy in animal models. Here, we investigated the effects of in vivo PZQ exposure on Schistosoma mansoni. Measurement of pro-apoptotic caspase activation revealed that worm death occurs only after parasites shift from the mesenteric vasculature to the liver, peaking 24 hours after drug treatment. This indicates that PZQ is not directly schistocidal, since PZQ's half-life is ~2 hours in humans and ~30 minutes in mice, and focuses attention on parasite interactions with the host immune system following the shift of worms to the liver. RNA-Seq of worms harvested from mouse livers following sub-lethal PZQ treatment revealed drug-evoked changes in the expression of putative immunomodulatory and anticoagulant gene products. Several of these gene products localized to the schistosome esophagus and may be secreted into the host circulation. These include several Kunitz-type protease inhibitors, which are also found in the secretomes of other blood feeding animals. These transcriptional changes may reflect mechanisms of parasite immune-evasion in response to chemotherapy, given the role of complement-mediated attack and the host innate/humoral immune response in parasite elimination. One of these isoforms, SmKI-1, has been shown to exhibit immunomodulatory and anti-coagulant properties. These data provide insight into the effect of in vivo PZQ exposure on S. mansoni, and the transcriptional response of parasites to the stress of chemotherapy. |
format |
Article in Journal/Newspaper |
author |
Paul McCusker Claudia M Rohr John D Chan |
author_facet |
Paul McCusker Claudia M Rohr John D Chan |
author_sort |
Paul McCusker |
title |
Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure. |
title_short |
Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure. |
title_full |
Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure. |
title_fullStr |
Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure. |
title_full_unstemmed |
Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure. |
title_sort |
schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2021 |
url |
https://doi.org/10.1371/journal.pntd.0009200 https://doaj.org/article/a01e036cacf64e4f84fcde1800ac27ae |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 15, Iss 3, p e0009200 (2021) |
op_relation |
https://doi.org/10.1371/journal.pntd.0009200 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009200 https://doaj.org/article/a01e036cacf64e4f84fcde1800ac27ae |
op_doi |
https://doi.org/10.1371/journal.pntd.0009200 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
15 |
container_issue |
3 |
container_start_page |
e0009200 |
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1766345237299462144 |