SIR2-Deficient Leishmania infantum Induces a Defined IFN-γ/ IL-10 Pattern That Correlates with Protection1

• Type: Article in International Scientific Journal
• Date: 2007

Authors

Ricardo Silvestre (Author) FFUP; Anabela Cordeiro-Da-Silva (Author) FFUP; Nuno Santarém (Author) Other; Baptiste Vergnes (Author) Other; Denis Sereno (Author) Other; Ali Ouaissi (Author) Other

Journal

Title: Journal of Immunology

Vol. 179 No. 5

Pages: 3161-3170

ISSN: 0022-1767

Publisher: American Association of Immunologists

Indexing

Pubmed / Medline

Scientific classification

FOS: Medical and Health sciences > Other medical sciences

CORDIS: Health sciences

Other information

Resumo (PT): The ability to manipulate the <i>Leishmania</i> 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 <i>Leishmania infantum</i> 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 <i>L. infantum</i> 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 <i>L. infantum</i> 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-<i> Leishmania</i> cytotoxic activity and high levels of NO production. Moreover, vaccinated mice simultaneously generated specific anti-<i>Leishmania</i> 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 <i>Leishmania</i> -specific IFN-γ/IL-10 ratio. Therefore, we propose that the polarization to a high IFN-γ/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. <br> <br> <a target="_blank" href="http://www.jimmunol.org/cgi/content/abstract/179/5/3161?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=silvestre%2C+r.&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT"> Texto integral</a> <br> <br>

Abstract (EN): The ability to manipulate the <i>Leishmania</i> 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 <i>Leishmania infantum</i> 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 <i>L. infantum</i> 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 <i>L. infantum</i> 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-<i> Leishmania</i> cytotoxic activity and high levels of NO production. Moreover, vaccinated mice simultaneously generated specific anti-<i>Leishmania</i> 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 <i>Leishmania</i> -specific IFN-γ/IL-10 ratio. Therefore, we propose that the polarization to a high IFN-γ/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. <br> <br> <a target="_blank" href="http://www.jimmunol.org/cgi/content/abstract/179/5/3161?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=silvestre%2C+r.&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT"> Full text </a> <br> <br>

Language: Portuguese

Type (Professor's evaluation): Scientific