Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacterial Toxins / metabolism
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Cell Line
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Cholesterol / metabolism
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Heat-Shock Proteins / metabolism
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Hemolysin Proteins / metabolism
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Interleukin-12 Subunit p40 / metabolism
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Listeria monocytogenes / drug effects*
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Listeria monocytogenes / metabolism
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Listeriosis / drug therapy
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Listeriosis / metabolism
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Liver / drug effects
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Liver / metabolism
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Liver / microbiology
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Macrophages / metabolism
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Macrophages / microbiology
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Mice
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Mice, Inbred C57BL
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Phagocytosis / drug effects
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Phagosomes / drug effects*
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Phagosomes / metabolism
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Simvastatin / pharmacology*
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Spleen / drug effects
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Spleen / metabolism
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Spleen / microbiology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Bacterial Toxins
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Heat-Shock Proteins
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Hemolysin Proteins
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Interleukin-12 Subunit p40
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Tumor Necrosis Factor-alpha
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Cholesterol
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Simvastatin
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hlyA protein, Listeria monocytogenes
Grants and funding
This work was supported by the International Centre for Genetic Engineering & Biotechnology (ICGEB), Cape Town with a PhD-fellowship to SPP, South African Medical Research Council (SAMRC) Unit on Immunology of Infectious Diseases (FB). A SAMRC self-initiated research grant (SIR), SAMRC research group development grant, University and Faculty Research Committee funding (URC/FRC) and grants from Kwazulu-Natal Research Institute for Tuberculosis and HIV (K-RITH) South Africa to RG, National Research Funding (NRF) South Africa and the South African Research Chair initiative (SARChi) to FB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.