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.
Highlights
Statins are inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA), a crucial enzyme in cholesterol biosynthesis pathway
Host defense against Listeria monocytogenes is increased by simvastatin treatment in mice
We investigated the effect of simvastatin treatment on bacterial burden during the acute phase of L. monocytogenes infection in mice
Summary
Statins are inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA), a crucial enzyme in cholesterol biosynthesis pathway. It has been observed that statin treatment can reduce mortality in patients with active bacteremia [2]. Apart from the ability of statins to decrease mortality in patients with cardiovascular diseases or bacteremia, studies have reported immunomodulatory and inflammatory properties of statins, independent of their ability to lower cholesterol levels [3,4]. A case study amongst US veterans showed that statin treatment reduced their risk of lung cancer [5]. Statins have been implicated in controlling Dengue virus replication in human PBMCs [6] and Epstein–Barr virus (EBV)-induced tumor formation in SCID mice was reduced following treatment with simvastatin, resulting in increased survival [7]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.