Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape

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dc.contributor.authorParihar, Suraj Pen_ZA
dc.contributor.authorGuler, Retoen_ZA
dc.contributor.authorLang, Dirk Men_ZA
dc.contributor.authorSuzuki, Harukazuen_ZA
dc.contributor.authorMarais, A Daviden_ZA
dc.contributor.authorBrombacher, Franken_ZA
dc.date.accessioned2016-01-11T06:53:23Z
dc.date.available2016-01-11T06:53:23Z
dc.date.issued2013en_ZA
dc.description.abstractStatins are well-known cholesterol lowering drugs targeting HMG-CoA-reductase, reducing the risk of coronary disorders and hypercholesterolemia. Statins are also involved in immunomodulation, which might influence the outcome of bacterial infection. Hence, a possible effect of statin treatment on Listeriosis was explored in mice. Statin treatment prior to subsequent L. monocytogenes infection strikingly reduced bacterial burden in liver and spleen (up to 100-fold) and reduced histopathological lesions. Statin-treatment in infected macrophages resulted in increased IL-12p40 and TNF-α and up to 4-fold reduced bacterial burden within 6 hours post infection, demonstrating a direct effect of statins on limiting bacterial growth in macrophages. Bacterial uptake was normal investigated in microbeads and GFP-expressing Listeria experiments by confocal microscopy. However, intracellular membrane-bound cholesterol level was decreased, as analyzed by cholesterol-dependent filipin staining and cellular lipid extraction. Mevalonate supplementation restored statin-inhibited cholesterol biosynthesis and reverted bacterial growth in Listeria monocytogenes but not in listeriolysin O (LLO)-deficient Listeria . Together, these results suggest that statin pretreatment increases protection against L. monocytogenes infection by reducing membrane cholesterol in macrophages and thereby preventing effectivity of the cholesterol-dependent LLO-mediated phagosomal escape of bacteria.en_ZA
dc.identifier.apacitationParihar, S. P., Guler, R., Lang, D. M., Suzuki, H., Marais, A. D., & Brombacher, F. (2013). Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape. <i>PLoS One</i>, http://hdl.handle.net/11427/16272en_ZA
dc.identifier.chicagocitationParihar, Suraj P, Reto Guler, Dirk M Lang, Harukazu Suzuki, A David Marais, and Frank Brombacher "Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape." <i>PLoS One</i> (2013) http://hdl.handle.net/11427/16272en_ZA
dc.identifier.citationParihar, S. P., Guler, R., Lang, D. M., Suzuki, H., Marais, A. D., & Brombacher, F. (2013). Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape. PloS one, 8(9), e75490. doi:10.1371/journal.pone.0075490en_ZA
dc.identifier.ris TY - Journal Article AU - Parihar, Suraj P AU - Guler, Reto AU - Lang, Dirk M AU - Suzuki, Harukazu AU - Marais, A David AU - Brombacher, Frank AB - Statins are well-known cholesterol lowering drugs targeting HMG-CoA-reductase, reducing the risk of coronary disorders and hypercholesterolemia. Statins are also involved in immunomodulation, which might influence the outcome of bacterial infection. Hence, a possible effect of statin treatment on Listeriosis was explored in mice. Statin treatment prior to subsequent L. monocytogenes infection strikingly reduced bacterial burden in liver and spleen (up to 100-fold) and reduced histopathological lesions. Statin-treatment in infected macrophages resulted in increased IL-12p40 and TNF-α and up to 4-fold reduced bacterial burden within 6 hours post infection, demonstrating a direct effect of statins on limiting bacterial growth in macrophages. Bacterial uptake was normal investigated in microbeads and GFP-expressing Listeria experiments by confocal microscopy. However, intracellular membrane-bound cholesterol level was decreased, as analyzed by cholesterol-dependent filipin staining and cellular lipid extraction. Mevalonate supplementation restored statin-inhibited cholesterol biosynthesis and reverted bacterial growth in Listeria monocytogenes but not in listeriolysin O (LLO)-deficient Listeria . Together, these results suggest that statin pretreatment increases protection against L. monocytogenes infection by reducing membrane cholesterol in macrophages and thereby preventing effectivity of the cholesterol-dependent LLO-mediated phagosomal escape of bacteria. DA - 2013 DB - OpenUCT DO - 10.1371/journal.pone.0075490 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape TI - Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape UR - http://hdl.handle.net/11427/16272 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16272
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0075490
dc.identifier.vancouvercitationParihar SP, Guler R, Lang DM, Suzuki H, Marais AD, Brombacher F. Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape. PLoS One. 2013; http://hdl.handle.net/11427/16272.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2013 Parihar et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherMacrophagesen_ZA
dc.subject.otherListeria monocytogenesen_ZA
dc.subject.otherStatinsen_ZA
dc.subject.otherCholesterolen_ZA
dc.subject.otherListeriaen_ZA
dc.subject.otherBacterial growthen_ZA
dc.subject.otherMouse modelsen_ZA
dc.subject.otherIntracellular membranesen_ZA
dc.titleSimvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escapeen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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