Lovastatin protects against experimental plague in mice.

Saravanan Ayyadurai,Michel Drancourt,Didier Raoult,Hubert Lepidi,Claude Nappez

doi:10.1371/journal.pone.0010928

Abstract

BackgroundPlague is an ectoparasite-borne deadly infection caused by Yersinia pestis, a bacterium classified among the group A bioterrorism agents. Thousands of deaths are reported every year in some African countries. Tetracyclines and cotrimoxazole are used in the secondary prophylaxis of plague in the case of potential exposure to Y. pestis, but cotrimoxazole-resistant isolates have been reported. There is a need for additional prophylactic measures. We aimed to study the effectiveness of lovastatin, a cholesterol-lowering drug known to alleviate the symptoms of sepsis, for plague prophylaxis in an experimental model.MethodologyLovastatin dissolved in Endolipide was intraperitoneally administered to mice (20 mg/kg) every day for 6 days prior to a Y. pestis Orientalis biotype challenge. Non-challenged, lovastatin-treated and challenged, untreated mice were also used as control groups in the study. Body weight, physical behavior and death were recorded both prior to infection and for 10 days post-infection. Samples of the blood, lungs and spleen were collected from dead mice for direct microbiological examination, histopathology and culture. The potential antibiotic effect of lovastatin was tested on blood agar plates.Conclusions/SignificanceLovastatin had no in-vitro antibiotic effect against Y. pestis. The difference in the mortality between control mice (11/15; 73.5%) and lovastatin-treated mice (3/15; 20%) was significant (P<0.004; Mantel-Haenszel test). Dead mice exhibited Y. pestis septicemia and inflammatory destruction of lung and spleen tissues not seen in lovastatin-treated surviving mice. These data suggest that lovastatin may help prevent the deadly effects of plague. Field observations are warranted to assess the role of lovastatin in the prophylaxis of human plague.

Highlights

Yersinia pestis is a Gram-negative bacillus belonging to the family Enterobacteriaceae
Y. pestis died within 48 hours post injection (p.i.), whereas 3/15 (20%) of the lovastatin group B mice died over a 10-day observation period (P,0.004) (Figure 1)
Because lovastatin is not readily soluble in aqueous solution, we dissolved it in Endolipide, a lipidic solution licensed for parenteral administration in humans

Summary

Introduction

Yersinia pestis is a Gram-negative bacillus belonging to the family Enterobacteriaceae. It is responsible for deadly bubonic, pneumonic and septicemic plagues [1,2] and is classified as a group A bioterrorism agent (CDC, Atlanta, GA). Clinical observations indicated that statins, which are competitive inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) [4,5], could prevent infections and reduced mortality during severe sepsis [6]. We tested whether lovastatin, a statin obtained from fungal fermentation, could significantly reduce the mortality associated with plague in an experimental mouse model. Plague is an ectoparasite-borne deadly infection caused by Yersinia pestis, a bacterium classified among the group A bioterrorism agents. We aimed to study the effectiveness of lovastatin, a cholesterol-lowering drug known to alleviate the symptoms of sepsis, for plague prophylaxis in an experimental model

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