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Comparative Evaluation of Two Vaccine Candidates against Experimental Leishmaniasis Due to Leishmania major Infection in Four Inbred Mouse Strains
Authors:Fouad Benhnini  Mehdi Chenik  Dhafer Laouini  Hechmi Louzir  Pierre André Cazenave  Koussay Dellagi
Abstract:Experimental leishmaniasis in BALB/c and C57BL/6 mice are the most investigated murine models that were used for the preclinical evaluation of Leishmania vaccine candidates. We have previously described two new inbred mouse strains named PWK and MAI issued from feral founders that also support the development of experimental leishmaniasis due to L. major. In this study, we sought to determine whether different mouse inbred strains generate concordant or discordant results when used to evaluate the potential of Leishmania proteins to protect against experimental leishmaniasis. To this end, two Leishmania proteins, namely, LACK (for Leishmania homolog of receptor for activated C kinase) and LmPDI (for L. major protein disulfide isomerase) were compared for their capacity to protect against experimental leishmaniasis in PWK, MAI, BALB/c, and C57BL/6 inbred mouse strains. Our data show that the capacity of Leishmania proteins to confer protection depends on the mouse strain used, stressing the important role played by the genetic background in shaping the immune response against the pathogen. These results may have important implications for the preclinical evaluation of candidate Leishmania vaccines: rather than using a single mouse strain, a panel of different inbred strains of various genetic backgrounds should be tested in parallel. The antigen that confers protection in the larger range of inbred strains may have better chances to be also protective in outbred human populations and should be selected for clinical trials.The leishmaniasis are parasitic diseases due to a protozoan of the genus Leishmania that are endemic in 88 countries. Three hundred and fifty million people are exposed to the infection risk and 14 million people are known to be infected. Two million new cases, including 1.5 million of the cutaneous leishmaniasis, are estimated to appear annually (39). The leishmaniasis represent a worldwide major public health problem because of several therapeutic challenges such as drug toxicity, parasite resistance to current drugs, and the high cost of the new treatments. The problem is particularly serious since the disease affects the poorest classes of the developing countries. The cutaneous leishmaniasis are among the rare parasitic diseases that might be potentially vaccine preventable. However, even if theoretically feasible, there is still no human Leishmania vaccine available today (17). One serious obstacle facing such a goal is the lack of experimental animal models that tightly mimic the disease as it occurs in humans.The experimental infection of inbred BALB/c and C57BL/6 mice by Leishmania major parasites has established the functionality of the Th1/Th2 dichotomy of CD4+ T helper cells and the contrasted pathogenic roles played in protection or disease promotion by the two Th subsets (33). Thus, C57BL/6 mice infected with L. major develop a Th1 response and efficiently control the disease within few weeks. In contrast, susceptible BALB/c mice mount a Th2 response and develop a severe, unremitting, and ultimately lethal disease (37). The susceptibility of BALB/c mice to L. major infection has been ascribed to the occurrence within the lymph nodes draining the inoculation site, of an early burst (at 16 h postinoculation) of interleukin-4 (IL-4) that polarizes the immune response toward the Th2 pathway (15, 24). The contrasted immunopathogenic mechanisms at work in BALB/c and C57BL/6 strains likely reflect differences in their genetic background. Since the majority of studies evaluating vaccine candidates have been conducted in the BALB/c model, it would be hazardous to extrapolate the conclusions drawn from these experiments to other inbred strains of different genetic backgrounds or to out bred animal models (i.e., primates): one given vaccine could be promising in one strain and still fail to protect in another strain (17). Thus, the criteria that would help to select at the preclinical stage a Leishmania antigen as a promising vaccine candidate worth entering the clinical trial stage are still not clearly defined.We have recently identified two new inbred mouse strains derived from feral founders, named PWK and MAI, that are susceptible to L. major infection (1). MAI mice develop an infiltrated lesion at the site of parasite inoculation that enlarges over time in an unremitted way. In this strain, the primary infection does not induce protection against reinfection. Although the immune response to Leishmania antigens in MAI mice was characterized by a Th2 cytokine profile, IL-4 did not seem to play a dominant role in disease phenotype as in BALB/c mice. In PWK mice, the experimental disease induced by L. major infection is featured by a nodule that develops at the site of parasite inoculation. This nodule is larger and of a much longer duration (30 weeks to complete healing) than the one that develops in C57BL/6. PWK mice acquire a solid immunity after a primary infection and are completely refractory to a secondary challenge. They develop during infection a mixed Th1/Th2 cytokine pattern, with IL-10 playing a disease-promoting role.The diverse disease patterns induced by L. major in PWK, MAI, C57BL/6, and BALB/c mice and the heterogeneity in the immunopathogenic mechanisms at work in each strain are likely shaped by the genetic background of the mice. This assumption led us to explore the effect of the genetic diversity of inbred mouse strains on the protection potentially conferred by Leishmania proteins against L major infection. Two Leishmania promising vaccine candidates were used, namely, the Leishmania homolog of receptor for activated C kinase (LACK) (31) and the L. major protein disulfide isomerase (LmPDI) (5).
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