Statins limit Rickettsia conorii infection in cells

Botelho-Nevers, Élisabeth; Rolain, Jean‐Marc; Espinosa, Léon; Raoult, Didier

doi:10.1016/j.ijantimicag.2008.04.027

Cited by 17 publications

(9 citation statements)

References 13 publications

(24 reference statements)

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“…R. felis California 2 strain (NC_007109), R. conorii Malish strain (ATCC VR-613), R. prowazekii Breinl strain (ATCC VR-142) and R. bellii RML 369-C strain (NC_007940.1; Rocky Mountain Laboratory Collection, Hamilton, Montana, U.S.A.) were cultured and used as previously described [31]. The R. felis genes vapB-1 (RF_0457), vapC-1 (RF_0456), vapB-2 (RF_ORF0094) and vapC-2 (RF_ORF0095) and the R. bellii genes vapC-1 (RBE_1021) and vapB-1 (RBE 1020) were amplified using genomic DNA as the template and cloned using a Gateway system (Invitrogen Ltd., Paisley, U.K.).…”

Section: Methodsmentioning

confidence: 99%

Effect of Rickettsial Toxin VapC on Its Eukaryotic Host

et al. 2011

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Rickettsia are intracellular bacteria typically associated with arthropods that can be transmitted to humans by infected vectors. Rickettsia spp. can cause mild to severe human disease with a possible protection effect of corticosteroids when antibiotic treatments are initiated. We identified laterally transferred toxin-antitoxin (TA) genetic elements, including vapB/C, in several Rickettsia genomes and showed that they are functional in bacteria and eukaryotic cells. We also generated a plaque assay to monitor the formation of lytic plaques over time and demonstrated that chloramphenicol accelerates host cell lysis of vapB/C-containing Rickettsia. Whole-genome expression, TUNEL and FISH assays on the infected cells following exposure to the antibiotic revealed early apoptosis of host cells, which was linked to over-transcription of bacterial vapB/C operons and subsequent cytoplasmic VapC toxin release. VapC that is expressed in Escherichia coli and Saccharomyces cerevisiae or microinjected into mammalian cells is toxic through RNase activity and is prevented by dexamethasone. This study provides the first biological evidence that toxin–antitoxin elements act as pathogenic factors in bacterial host cells, confirming comparative genomic evidence of their role in bacterial pathogenicity. Our results suggest that early mortality following antibiotic treatment of some bacterial infections can be prevented by administration of dexamethasone.

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Section: Methodsmentioning

confidence: 99%

Effect of Rickettsial Toxin VapC on Its Eukaryotic Host

et al. 2011

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“…Recent reports demonstrated that lovastatin at 0.4 mg/liter (53) and both atorvastatin and simvastatin, in a dose-dependent fashion (0.08 to 0.8 mg/ liter), reduced the survival of the leprosy-causing species Mycobacterium leprae (by up to 90% and 75%, respectively) in in vitro macrophage models, but in a cholesterol-dependent manner (54), suggesting an indirect effect on cholesterol levels, as the intracellular growth of these pathogens requires cholesterol. Prior but not concurrent treatment of murine fibroblast (L929) cells with lovastatin at 0.4 mg/liter also reduced both the intracellular growth of the respiratory pathogen Coxiella burnetii (which causes Q fever) (by 43%, P ϭ 0.064) (55) and plaque formation by the causative agent of Rocky mountain spotted fever, Rickettsia conorii (by 64%, P ϭ 0.003) (56). Interestingly, in in vivo studies, administration of the hydrophobic statin simvastatin, at a physiological concentration (0.5 mg/kg of body weight), but not administration of the hydrophilic statin pravastatin, significantly decreased (up to 83%) the levels of the respiratory pathogen Chlamydiae pneumoniae in lung cells of infected mice (57,58).…”

Section: Effects Of Statins On Intracellular Growth Of Bacteriamentioning

confidence: 98%

“…However, statins are known to inhibit the formation of lipid rafts due to inhibition of cholesterol biosynthesis (44). Two studies investigating the effects of statins on intracellular growth of L. monocytogenes and plaque formation of R. conorii suggest that their findings were due to the inhibition of lipid raft formation by statins (56,61).…”

Section: Effects Of Statins On Intracellular Growth Of Bacteriamentioning

confidence: 99%

Is There Potential for Repurposing Statins as Novel Antimicrobials?

Hennessy

Adams

Reen

et al. 2016

Antimicrob Agents Chemother

108

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bStatins are members of a class of pharmaceutical widely used to reduce high levels of serum cholesterol. In addition, statins have so-called "pleiotropic effects," which include inflammation reduction, immunomodulation, and antimicrobial effects. An increasing number of studies are emerging which detail the attenuation of bacterial growth and in vitro and in vivo virulence by statin treatment. In this review, we describe the current information available concerning the effects of statins on bacterial infections and provide insight regarding the potential use of these compounds as antimicrobial therapeutic agents. O ne of the major undisputed clinical breakthroughs of the 20th century was the discovery of the statin family of drugs. These compounds are renowned for their ability to lower cholesterol levels and are used to treat approximately 40 million individuals with high cholesterol levels worldwide. Since the discovery of mevastatin as a metabolic product of Penicillium citrinum in 1976 (1, 2), a total of nine statins have been characterized, seven of which are approved by the FDA to treat patients with high cholesterol. Structurally, statins are characterized by the presence of a conserved lactone ring (3). This structure is present as a hydrolyzed (active) form in all statins except for mevastatin, lovastatin, and simvastatin; in those statins, the lactone ring is hydrolyzed in the liver (4). Statins can be divided into two broad classes (Fig. 1). Type 1 statins are lipophilic and possess a butyryl side chain-they are said to structurally resemble mevastatin (3). Lovastatin, pravastatin, and simvastatin are type 1 statins. Type 2 statins are classically lipophobic and are distinguished from type 1 by the replacement of the butyryl side chain with a fluorophenol group and typically possess larger side chains than type 1 statins (3). Atorvastatin, cerivastatin, fluvastatin, pitavastatin, and rosuvastatin are type 2 statins.Statins exert their cholesterol-lowering effect by binding to the active site of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR), a rate-limiting enzyme involved in cholesterol biosynthesis (3). HMGR is an integral part of the mevalonate pathway, which not only is essential for cholesterol biosynthesis but also contributes to the production of isoprenoids, lipid compounds that are essential for cell signaling and structure. As well as inhibition of cholesterol, statins have also been found to have a number of cholesterol-independent, socalled "pleiotropic" effects. Statins have been reported to confer anti-inflammatory, immunomodulatory, and anticancer effects on host cells, and these effects are well characterized (5-9). Furthermore, several studies have explored the pleiotropic effects of statins in combating multisystem microbial infections, such as sepsis and pneumonia, and a growing number of studies are demonstrating that statins can directly influence the growth and virulence of bacterial pathogens. With the global increase in antibiotic resistance to existing antib...

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“…Lovastatin inhibits intracellular replication of C. burnettii likely through reduction of cholesterol in the parasitophorous vacuole membrane, potentially at concentrations achievable in the serum of patients [155]. Similar results are found with R. conorii infection [156]. Statins also inhibit intracellular replication of Salmonella within macrophages, leading to reduced infectious burden in vivo in mice [157].…”

Section: A Role For Statins In Host Defense?mentioning

confidence: 85%

Roles of the Mevalonate Pathway and Cholesterol Trafficking in Pulmonary Host Defense

Gabor¹,

Fessler

2017

CMP

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It has become increasingly recognized that cholesterol and lipoproteins play significant roles in both lung physiology and the innate immune response. It is now known that the innate immune response and the cholesterol biosynthesis/trafficking network regulate one another, with important implications for pathogen invasion and host defense. The activation of pathogen recognition receptors and downstream cellular host defense functions are critically sensitive to cellular cholesterol. Conversely, microorganisms can co-opt the sterol/lipoprotein network in order to facilitate their own replication. Given that over 50% of adults in the U.S. have cholesterol abnormalities and pneumonia remains a leading cause of death, the potential impact of cholesterol on pulmonary host defense is of tremendous public health significance. This review addresses the emerging link between the innate immune response and sterol homeostasis, with a focus upon implications for respiratory infection. Clinical translations, including in the area of potential therapeutic development for infectious lung disease, are also discussed.

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Statins limit Rickettsia conorii infection in cells

Cited by 17 publications

References 13 publications

Effect of Rickettsial Toxin VapC on Its Eukaryotic Host

Effect of Rickettsial Toxin VapC on Its Eukaryotic Host

Is There Potential for Repurposing Statins as Novel Antimicrobials?

Roles of the Mevalonate Pathway and Cholesterol Trafficking in Pulmonary Host Defense

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