Lovastatin protects against experimental plague in mice

Abstract

Background: Plague 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.

Methodology: Lovastatin 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/significance: Lovastatin 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.

Figure 1. Histogram of mortality in groups of 15 mice challenged with Y. pestis and injected with PBS (group A) or lovastatin (group B); or challenged with lovastatin only (group C).

Figure 2. Acridine orange staining of blood from dead group B mice (a; original magnification, 100×) showing Y. pestis organisms.

No organisms were found in the blood of the lovastatin-treated mice that survived the Y. pestis challenge (b; original magnification, 100×).

Figure 3. HES staining of lung tissue (a; original magnification, 100×) and spleen tissue (b; original magnification ×50) from group B mice after lovastatin prophylaxis and Y. pestis challenge.

No pathological changes were observed; particularly, no inflammatory infiltrates or necrotic areas were detected.