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/IL-10 Pattern That Correlates with Protection1
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* Departamento de Bioquímica da Faculdade de Farmácia da Universidade do Porto, Portugal;
Instituto de Biologia Molecular e Celular da Universidade do Porto, Portugal;
Institut National de la Santé et de la Recherche Médicale (INSERM); and
Institut de Recherche pour le Développement (IRD), Centre IRD de Montpellier, Montpellier, France
The ability to manipulate the Leishmania genome to create genetically modified parasites by introducing or eliminating genes is considered a powerful alternative for developing a new generation vaccine against leishmaniasis. Previously, we showed that the deletion of one allele of the Leishmania infantum silent information regulatory 2 (LiSIR2) locus was sufficient to dramatically affect amastigote axenic proliferation. Furthermore, LiSIR2 single knockout (LiSIR2+/–) amastigotes were unable to replicate in vitro inside macrophages. Because this L. infantum mutant persisted in BALB/c mice for up to 6 wk but failed to establish an infection, we tested its ability to provide protection toward a virulent L. infantum challenge. Strikingly, vaccination with a single i.p. injection of LiSIR2+/– single knockout elicits complete protection. Thus, vaccinated BALB/c mice showed a reversal of T cell anergy with specific anti-Leishmania cytotoxic activity and high levels of NO production. Moreover, vaccinated mice simultaneously generated specific anti-Leishmania IgG Ab subclasses suggestive of both type 1 and type 2 responses. A strong correlation was found between the elimination of the parasites and an increased Leishmania-specific IFN-
/IL-10 ratio. Therefore, we propose that the polarization to a high IFN-/low IL-10 ratio after challenge is a clear indicator of vaccine success. Furthermore these mutants, which presented attenuated virulence, represent a good model to understand the correlatives of protection in visceral leishmaniasis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Fundação para a Ciência e Tecnologia (FCT) and European Regional Development Fund (FEDER) Grants POCTI/CVT/39257/2001 and POCI/CVT/59840/2004, INSERM and IRD UR008. R.S. and N.S. are supported by a fellowship from FCT and FEDER Grants SFRH/BD/13120/2003 and POCI/SAU-FCT/59837/2004, respectively.
2 Address correspondence and reprint requests to Dr. Ali Ouaissi, INSERM, IRD, UR008 Centre de Montpellier, 911 Avenue Agropolis, Montpellier, France. E-mail address: ali.ouaissi{at}montp.inserm.fr
3 Abbreviations used in this paper: LiSIR2, Leishmania infantum silent information regulatory 2 parasite; LiSIR2+/–, LiSIR2 single knockout parasite; RPMIc, complete RPMI 1640 medium; SLA, soluble Leishmania Ag; WT, wild type.
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