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 (day0) 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.
Highlights
Cutaneous leishmaniasis (CL) manifests as a localized self-healing lesion(s) that in rare cases develops to a non-healing lesion
C57BL/6 mice were inoculated with transgenic lmtkcd+/+strain; the rate of protection, parasite burden and the type of immune response were checked, and the results showed that complete protection induced by inoculation of lmtkcd+/+strain if treatment is initiated on day 8 post inoculation
The group of mice inoculated with wild type (WT) L. major which was treated with GCV/5-FCyt developed a lesion similar to the untreated group of mice (Fig. 1A)
Summary
Cutaneous leishmaniasis (CL) manifests as a localized self-healing lesion(s) that in rare cases develops to a non-healing lesion. Leishmanization (LZ) involves inoculating of individuals with live virulent Leishmania major to induce a single lesion that mimics a natural infection but with the lesion located at a predetermined site. LZ has been shown to be the most effective control measure at least against CL but the practice has been discontinued except on a limited scale in Uzbekistan. This is due to the development of chronic lesions that require medical intervention [7,8,9]. One approach is to derive attenuated live vaccine strains of Leishmania through genetic manipulation to develop a parasite strain which has no virulence or a limited pathogenicity.
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