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

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.

• Authors: Suraj P Parihar, Reto Guler, Dirk M Lang, Harukazu Suzuki, A David Marais, Frank Brombacher
• Journal: PloS one (PLoS One) Vol. 8 Issue 9 Pg. e75490 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24086542 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Toxins
• Heat-Shock Proteins
• Hemolysin Proteins
• Interleukin-12 Subunit p40
• Tumor Necrosis Factor-alpha
• Cholesterol
• Simvastatin
• hlyA protein, Listeria monocytogenes

Topics

• Animals
• Bacterial Toxins (metabolism)
• Cell Line
• Cholesterol (metabolism)
• Heat-Shock Proteins (metabolism)
• Hemolysin Proteins (metabolism)
• Interleukin-12 Subunit p40 (metabolism)
• Listeria monocytogenes (drug effects, metabolism)
• Listeriosis (drug therapy, metabolism)
• Liver (drug effects, metabolism, microbiology)
• Macrophages (metabolism, microbiology)
• Mice
• Mice, Inbred C57BL
• Phagocytosis (drug effects)
• Phagosomes (drug effects, metabolism)
• Simvastatin (pharmacology)
• Spleen (drug effects, metabolism, microbiology)
• Tumor Necrosis Factor-alpha (metabolism)