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THE F1F3 RECOMBINANT CHIMERA OF LEISHMANIA DONOVANI-NUCLEOSIDE HYDROLASE (NH36) AND ITS EPITOPES INDUCE CROSS-PROTECTION AGAINST LEISHMANIA (V.) BRAZILIENSIS INFECTION IN MICE
Leishmaniose cutânea
Leishmaniose mucocutânea
Nucleosídeo hidrolase NH36
Quimera F1F3 recombinante
Resposta regulatória mista ou de células T
Leishmania (V.) braziliensis
Mucocutaneous leishmaniasis
Nucleoside hydrolase NH36
F1F3 recombinant chimera
Mixed or T-cell regulatory response
Affilliation
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Biologia e Bioquímica de Leishmania. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Programa de Pós-Graduação em Biotecnologia Vegetal e Bioprocessos. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Biologia e Bioquímica de Leishmania. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de |Imunofarmacologia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Biologia e Bioquímica de Leishmania. Rio de Janeiro, RJ, Brasil / Universidade de São Paulo. Faculdade de Medicina. Instituto de Investigação em Imunologia. São Paulo, SP, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Biologia e Bioquímica de Leishmania. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de |Imunofarmacologia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Biologia e Bioquímica de Leishmania. Rio de Janeiro, RJ, Brasil / Universidade de São Paulo. Faculdade de Medicina. Instituto de Investigação em Imunologia. São Paulo, SP, Brasil.
Abstract
Leishmania (V.) braziliensis is the etiological agent of Cutaneous (CL) andMucocutaneous
leishmaniasis (ML) in the New World. CL can be more benign but ML can be severe
and disfiguring. Immunity to these diseases include hypersensitivity, an enhanced
inflammatory response with strong IFN-g and TNF-a secretion. Additionally, the
production of IL-10 which down modulates the immune response is reduced. The
Nucleoside hydrolase (NH36) of Leishmania (L.) donovani is the main antigen of the
Leishmune veterinary vaccine and its F3 domain induces a CD4+ T cell-mediated
protection against L. (L.) infantum chagasi infection. Prevention of L. (L.) amazonensis
infection requires in contrast an additional CD8+ T cellmediated response induced by the
F1 domain. Consequently, the F1F3 recombinant chimera, which contains both domains
cloned in tandem, optimized the vaccine efficacy against L. (L.) amazonensis mouse
infection. We compared the efficacies of NH36, F1, F3, and the FIF3 chimera against L.
(V.) braziliensis mouse infection. The F1F3 chimera increased the NH36 specific IgA and
response before and after infection and the IgG and IgG3 levels after challenge. It also
induced a 49%stronger intradermal response to leishmanial antigen (IDR) than NH36 that
was positively correlated to the levels of IFN-g and TNF-a, IgG, IgG2a, IgG2b, and IgG3
anti-NH36 antibodies. However, stronger Th1 responses with elevated IFN-g/IL-10 and
TNF-a/IL-10 ratios were promoted by the F3 and F1 vaccines and detected in infected
controls while the F1F3 chimera promoted the highest IL-10 secretion, which reduced
the pathological Th1 response, and characterized the induction of a mixed and/or T-cell
regulatory response.We identified the epitopes responsible for these immune responses.
The F3 vaccine induced the earliest immunity and after challenge, the F1F3 chimera promoted the highest CD4+ and CD8+ cytokine-secreting T cell responses, and the
predominant frequencies of multifunctional CD4+ and CD8+IL-2+TNF-a+IFN-g+ T cells. Also as observed against L. (L.) amazonensis infection, the F1F3 chimera showed the
strongest reduction of the ear lesions sizes induced by L. (V.) braziliensis. Our results
confirm the potential use of the F1F3 chimera in a multi-species cross-protective vaccine
against L. (V.) braziliensis.
Keywords in Portuguese
Leishmania (V.) braziliensisLeishmaniose cutânea
Leishmaniose mucocutânea
Nucleosídeo hidrolase NH36
Quimera F1F3 recombinante
Resposta regulatória mista ou de células T
Keywords
Cutaneous leishmaniasisLeishmania (V.) braziliensis
Mucocutaneous leishmaniasis
Nucleoside hydrolase NH36
F1F3 recombinant chimera
Mixed or T-cell regulatory response
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