Simvastatin Enhances Protection against Listeria monocytogenes Infection in Mice by Counteracting Listeria-Induced Phagosomal Escape: e75490

• Published in: PloS one Vol. 8; no. 9
• Main Authors: Parihar, Suraj P, Guler, Reto, Lang, Dirk M, Suzuki, Harukazu, Marais, A David, Brombacher, Frank
• Format: Journal Article
• Language: English
• Published: 01-09-2013
• Subjects: Cholesterol; Listeria monocytogenes
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0075490

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- alpha 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.