Adaptive Immunity against Leishmania Nucleoside Hydrolase Maps Its C-Terminal Domain as the Target of the CD4+ T Cell-Driven Protective Response

Adaptive Immunity against Leishmania Nucleoside Hydrolase Maps Its C-Terminal Domain as the Target of the CD4+ T Cell-Driven Protective Response

Author Nico, Dirlei Google Scholar
Claser, Carla Autor UNIFESP Google Scholar
Borja-Cabrera, Gulnara P. Google Scholar
Travassos, Luiz R. Autor UNIFESP Google Scholar
Palatnik, Marcos Google Scholar
Soares, Irene da Silva Google Scholar
Rodrigues, Mauricio Martins Autor UNIFESP Google Scholar
Palatnik-de-Sousa, Clarisa B. Google Scholar
Institution Universidade Federal do Rio de Janeiro (UFRJ)
Universidade Federal de São Paulo (UNIFESP)
Universidade de São Paulo (USP)
Abstract Nucleoside hydrolases (NHs) show homology among parasite protozoa, fungi and bacteria. They are vital protagonists in the establishment of early infection and, therefore, are excellent candidates for the pathogen recognition by adaptive immune responses. Immune protection against NHs would prevent disease at the early infection of several pathogens. We have identified the domain of the NH of L. donovani (NH36) responsible for its immunogenicity and protective efficacy against murine visceral leishmaniasis (VL). Using recombinant generated peptides covering the whole NH36 sequence and saponin we demonstrate that protection against L. chagasi is related to its C-terminal domain (amino-acids 199-314) and is mediated mainly by a CD4+ T cell driven response with a lower contribution of CD8+ T cells. Immunization with this peptide exceeds in 36.73 +/- 12.33% the protective response induced by the cognate NH36 protein. Increases in IgM, IgG2a, IgG1 and IgG2b antibodies, CD4+ T cell proportions, IFN-gamma secretion, ratios of IFN-gamma/IL-10 producing CD4+ and CD8+ T cells and percents of antibody binding inhibition by synthetic predicted epitopes were detected in F3 vaccinated mice. the increases in DTH and in ratios of TNF alpha/IL-10 CD4+ producing cells were however the strong correlates of protection which was confirmed by in vivo depletion with monoclonal antibodies, algorithm predicted CD4 and CD8 epitopes and a pronounced decrease in parasite load (90.5-88.23%; p = 0.011) that was long-lasting. No decrease in parasite load was detected after vaccination with the N-domain of NH36, in spite of the induction of IFN-gamma/IL-10 expression by CD4+ T cells after challenge. Both peptides reduced the size of footpad lesions, but only the C-domain reduced the parasite load of mice challenged with L. amazonensis. the identification of the target of the immune response to NH36 represents a basis for the rationale development of a bivalent vaccine against leishmaniasis and for multivalent vaccines against NHs-dependent pathogens.
Language English
Sponsor Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)
Grant number CNPq: 500992/2008-8
FAPERJ: E-26/110305/2007
FAPERJ: E-26/110132/2007
FAPERJ: E-26/100416/2007
FAPERJ: E-26/102733/2008
Date 2010-11-01
Published in Plos Neglected Tropical Diseases. San Francisco: Public Library Science, v. 4, n. 11, 13 p., 2010.
ISSN 1935-2735 (Sherpa/Romeo, impact factor)
Publisher Public Library Science
Extent 13
Origin http://dx.doi.org/10.1371/journal.pntd.0000866
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000284765900009
URI http://repositorio.unifesp.br/handle/11600/33015

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