title: A dual drug sensitive L. major induces protection without lesion in C57BL/6 mice.
abstract: Leishmaniasis is a major health problem in some endemic areas and yet, no vaccine is available against any form of the disease. Historically, leishmanization (LZ) which is an inoculation of individual with live Leishmania, is the most effective control measure at least against cutaneous leishmaniasis (CL). Due to various reasons, LZ is not used today. Several live attenuated Leishmania have been developed but their use is limited. Previously, we developed a transgenic strain of L. major that harbors two suicide genes tk and cd genes (lmtkcd+/+) for use as a challenge strain in vaccine studies. These genes render the parasite susceptible to Ganciclovir (GCV) and 5-flurocytosine (5-FC). The dual drug sensitive strain of L. major was developed using gene targeting technology using a modified Herpes Simplex Virus thymidine kinase gene (hsv-tk) sensitive to Ganciclovir antibiotic and Saccharomyces cerevisae cytosine deaminase gene (cd sensitive to 5-flurocytosine) that were stably introduced into L. major chromosome. BALB/c mice inoculated with lmtkcd+/+ developed lesions which upon treatment with GCV and 5-FC completely healed. In the current study, the transgenic lmtkcd+/+strain was assessed as a live vaccine model to determine the time necessary to develop a protective immune response. C57BL/6 mice were inoculated with the transgenic lmtkcd+/+strain, and treated at the time of inoculation (day 0) or at day 8 after inoculation. Immunized animals were challenged with wild-type L. major, and complete protection was induced in mice that were treated at day 8. The results show that in contrast to leishmanization, in group of mice inoculated with a dual sensitive L. major development and persistence of lesion is not necessary to induce Th1 response and protection.
authors.affiliation: Biotechnology Research Center, Dept of Medical Biotechnology, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: Noushin
authors.initials: N
authors.lastname: Davoudi
authors.affiliation: Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Khamesipour
authors.affiliation: Biotechnology Research Center, Dept of Medical Biotechnology, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: Fereidoun
authors.initials: F
authors.lastname: Mahboudi
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada.
authors.forename: W Robert
authors.initials: WR
authors.lastname: McMaster
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000981:Antiprotozoal Agents / Q000494:pharmacology; D005260:Female; D005437:Flucytosine / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D007074:Immunoglobulin G / Q000097:blood; D018320:Leishmania major / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D054332:Leishmaniasis Vaccines / Q000235:genetics / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D030781:Organisms, Genetically Modified / Q000235:genetics / Q000276:immunology; D059208:Parasite Load
chemical_list: D000913:Antibodies, Protozoan; D000981:Antiprotozoal Agents; D007074:Immunoglobulin G; D054332:Leishmaniasis Vaccines; D005437:Flucytosine; D015774:Ganciclovir