title: Topical Simvastatin as Host-Directed Therapy against Severity of Cutaneous Leishmaniasis in Mice.
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.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.|Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa.
authors.forename: Suraj P
authors.initials: SP
authors.lastname: Parihar
authors.affiliation: Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, Epalinges, CH1066, Switzerland.
authors.forename: Mary-Anne
authors.initials: MA
authors.lastname: Hartley
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.|Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa.|Department of Molecular and Cell Biology, Faculty of Science, University of Cape Town, Rondebosch-7701, Cape Town, South Africa.
authors.forename: Ramona
authors.initials: R
authors.lastname: Hurdayal
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.|Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa.
authors.forename: Reto
authors.initials: R
authors.lastname: Guler
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.|Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa.
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
mesh_terms: D000287:Administration, Topical; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006861:Hydrogen Peroxide / Q000378:metabolism; D018320:Leishmania major / Q000187:drug effects; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010271:Parasites / Q000187:drug effects; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D012720:Severity of Illness Index; D019821:Simvastatin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D019821:Simvastatin; D006861:Hydrogen Peroxide