Topical Simvastatin as Host-Directed Therapy against Severity of Cutaneous Leishmaniasis in Mice.

Suraj P Parihar,Mary-Anne Hartley,Frank Brombacher,Ramona Hurdayal,Reto Guler

doi:10.1038/srep33458

Abstract

We recently demonstrated that statins mediate protection against intracellular pathogens, Mycobacterium tuberculosis and Listeria monocytogenes in mice. Here, we investigated the immunomodulatory potential of simvastatin as a topical or systemic host-directed drug therapy in controlling inflammatory responses in an experimental mouse model of cutaneous leishmaniasis caused by Leishmania major (LV39). In an ear infection model, topical application of simvastatin directly on established lesions significantly reduced severity of the disease reflected by ear lesion size and ulceration. The host protective effect was further accompanied by decreased parasite burden in the ear and draining lymph nodes in both BALB/c and C57BL/6 mice. Pre-treatment of these mice on a low-fat cholesterol diet and systemic simvastatin also reduced footpad swelling, as well as parasite burdens and ulceration/necrosis in the more robust footpad infection model, demonstrating the prophylactic potential of simvastatin for cutaneous leishmaniasis. Mechanistically, following L. major infection, simvastatin-treated primary macrophages responded with significantly reduced cholesterol levels and increased production of hydrogen peroxide. Furthermore, simvastatin-treated macrophages displayed enhanced phagosome maturation, as revealed by increased LAMP-3 expression in fluorescent microscopy and Western blot analysis. These findings demonstrate that simvastatin treatment enhances host protection against L. major by increasing macrophage phagosome maturation and killing effector functions.

Highlights

Leishmaniasis is a neglected human parasitic disease of the tropic
Topical application of simvastatin on ear lesions caused by Leishmania major is therapeutic in both BALB/c and C57BL/6 mice
With 1×103 parasites infection in BALB/c mice, we found that our daily regimen of topical simvastatin treatment (Fig. 1a) resulted in visibly decreased ear swelling (Fig. 1b) and ulceration (Fig. 1g), which was further accompanied by reduced parasite burdens in the ear and cervical lymph nodes (LN) (Fig. 1c) after 10 weeks of infection

Summary

Introduction

Leishmaniasis is a neglected human parasitic disease of the tropic. A haematophagous sand fly vectors the Leishmania parasite, and its numerous species give rise to a variety of clinical manifestations, ranging from localised, disfiguring inflammatory skin lesions to fatal visceral forms. There are no effective vaccines and current first-line therapies are based on an antiquated arsenal of pathogen-directed drugs, such as pentavalent antimonials. Host-directed immunotherapeutic have the major advantage of reducing the potential emergence of drug-resistance[4] and may interfere with the complex of immune evasion which Leishmania parasites has developed in order to promote its survival within the phagolysosome of host macrophages. One such evasion mechanism is the parasite’s ability to reduce macrophage activation by manipulating membrane cholesterol in host cells[5]. Pre-treatment of primary macrophages with simvastatin resulted in increased production of hydrogen peroxide and phagosome maturation, leading to enhanced killing effector functions

Methods

Results

Conclusion