SIR2-deficient Leishmania infantum induces a defined IFN-gamma/IL-10 pattern that correlates with protection.
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-gamma/IL-10 ratio. Therefore, we propose that the polarization to a high IFN-gamma/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.
Silvestre
Ricardo
R
Departamento de Bioquímica da Faculdade de Farmácia da Universidade do Porto, Portugal.
Cordeiro-Da-Silva
Anabela
A
Santarém
Nuno
N
Vergnes
Baptiste
B
Sereno
Denis
D
Ouaissi
Ali
A
D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D017635:Clonal Anergy; D017353:Gene Deletion; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D018314:Leishmania infantum / Q000235:genetics* / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000517:prevention & control*; D008099:Liver / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D015800:Protozoan Proteins / Q000235:genetics*; D016052:Protozoan Vaccines / Q000235:genetics* / Q000276:immunology*; D037761:Sirtuins / Q000235:genetics*; D013154:Spleen / Q000469:parasitology; D013601:T-Lymphocytes / Q000276:immunology; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology; D014774:Virulence / Q000235:genetics
D000913:Antibodies, Protozoan; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; D014613:Vaccines, Attenuated; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma; D037761:Sirtuins