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Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin

Sholeem Griffin, Giulio Preta, Iain Martin Sheldon, Martin Sheldon Orcid Logo

Scientific Reports, Volume: 7, Issue: 1, Pages: 1 - 13

Swansea University Author: Martin Sheldon Orcid Logo

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DOI (Published version): 10.1038/s41598-017-17138-y

Abstract

Animal health depends on the ability of immune cells to kill invading pathogens, and on the resilience of tissues to tolerate the presence of pathogens. Trueperella pyogenes causes tissue pathology in many mammals by secreting a cholesterol-dependent cytolysin, pyolysin (PLO), which targets stromal...

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Published in: Scientific Reports
ISSN: 2045-2322
Published: 2017
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URI: https://cronfa.swan.ac.uk/Record/cronfa37344
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first_indexed 2017-12-12T13:49:42Z
last_indexed 2020-07-14T13:03:48Z
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spelling 2020-07-14T11:01:38.2006024 v2 37344 2017-12-06 Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin ab0f74b794e59cc270c69e63ee1d9748 0000-0001-7902-5558 Martin Sheldon Martin Sheldon true false 2017-12-06 BMS Animal health depends on the ability of immune cells to kill invading pathogens, and on the resilience of tissues to tolerate the presence of pathogens. Trueperella pyogenes causes tissue pathology in many mammals by secreting a cholesterol-dependent cytolysin, pyolysin (PLO), which targets stromal cells. Cellular cholesterol is derived from squalene, which is synthesized via the mevalonate pathway enzymes, including HMGCR, FDPS and FDFT1. The present study tested the hypothesis that inhibiting enzymes in the mevalonate pathway to reduce cellular cholesterol increases the resilience of stromal cells to PLO. We first verified that depleting cellular cholesterol with methyl-β-cyclodextrin increased the resilience of stromal cells to PLO. We then used siRNA to deplete mevalonate pathway enzyme gene expression, and used pharmaceutical inhibitors, atorvastatin, alendronate or zaragozic acid to inhibit the activity of HMGCR, FDPS and FDFT1, respectively. These approaches successfully reduced cellular cholesterol abundance, but mevalonate pathway enzymes did not affect cellular resilience equally. Inhibiting FDFT1 was most effective, with zaragozic acid reducing the impact of PLO on cell viability. The present study provides evidence that inhibiting FDFT1 increases stromal cell resilience to a cholesterol-dependent cytolysin. Journal Article Scientific Reports 7 1 1 13 2045-2322 Cellular microbiology, Infection, Reproductive biology 6 12 2017 2017-12-06 10.1038/s41598-017-17138-y COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University RCUK, BBSRC, BB/K006592/1 2020-07-14T11:01:38.2006024 2017-12-06T15:08:15.6916456 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Sholeem Griffin 1 Giulio Preta 2 Iain Martin Sheldon 3 Martin Sheldon 0000-0001-7902-5558 4 0037344-06122017150904.pdf Griffin.pdf 2017-12-06T15:09:04.9730000 Output 2342652 application/pdf Version of Record true 2017-12-06T00:00:00.0000000 This article is licensed under a Creative Commons Attribution 4.0 International License. true eng
title Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin
spellingShingle Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin
Martin Sheldon
title_short Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin
title_full Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin
title_fullStr Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin
title_full_unstemmed Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin
title_sort Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin
author_id_str_mv ab0f74b794e59cc270c69e63ee1d9748
author_id_fullname_str_mv ab0f74b794e59cc270c69e63ee1d9748_***_Martin Sheldon
author Martin Sheldon
author2 Sholeem Griffin
Giulio Preta
Iain Martin Sheldon
Martin Sheldon
format Journal article
container_title Scientific Reports
container_volume 7
container_issue 1
container_start_page 1
publishDate 2017
institution Swansea University
issn 2045-2322
doi_str_mv 10.1038/s41598-017-17138-y
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Animal health depends on the ability of immune cells to kill invading pathogens, and on the resilience of tissues to tolerate the presence of pathogens. Trueperella pyogenes causes tissue pathology in many mammals by secreting a cholesterol-dependent cytolysin, pyolysin (PLO), which targets stromal cells. Cellular cholesterol is derived from squalene, which is synthesized via the mevalonate pathway enzymes, including HMGCR, FDPS and FDFT1. The present study tested the hypothesis that inhibiting enzymes in the mevalonate pathway to reduce cellular cholesterol increases the resilience of stromal cells to PLO. We first verified that depleting cellular cholesterol with methyl-β-cyclodextrin increased the resilience of stromal cells to PLO. We then used siRNA to deplete mevalonate pathway enzyme gene expression, and used pharmaceutical inhibitors, atorvastatin, alendronate or zaragozic acid to inhibit the activity of HMGCR, FDPS and FDFT1, respectively. These approaches successfully reduced cellular cholesterol abundance, but mevalonate pathway enzymes did not affect cellular resilience equally. Inhibiting FDFT1 was most effective, with zaragozic acid reducing the impact of PLO on cell viability. The present study provides evidence that inhibiting FDFT1 increases stromal cell resilience to a cholesterol-dependent cytolysin.
published_date 2017-12-06T03:47:01Z
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