Surface expression of an immunodominant malaria protein B cell epitope by yellow fever virus

Surface expression of an immunodominant malaria protein B cell epitope by yellow fever virus

Autor Bonaldo, M. C. Google Scholar
Garratt, R. C. Google Scholar
Caufour, P. S. Google Scholar
Freire, M. S. Google Scholar
Rodrigeus, M. M. Google Scholar
Nussenzweig, R. S. Google Scholar
Galler, R. Google Scholar
Instituição Fdn Oswaldo Cruz
Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
NYU
Resumo The yellow fever 17D virus (YF17D) has several characteristics that are desirable for the development of new, live attenuated vaccines. We approached its development as a vector for heterologous antigens by studying the expression of a humoral epitope at the surface of the E protein based on the results of modelling its three-dimensional structure. This model indicated that the most promising insertion site is between beta-strands f and g, a site that is exposed at the external surface of the virus. the large deletion of six residues from the fg loop of the E protein,, from yellow fever virus, compared to tick-born encephalitis virus, leaves, space at the dimer interface for a large insertion without creating steric hindrance. We have tested this hypothesis by inserting a model humoral epitope from the circurnsporozoite protein of Plasmodium falciparian consisting of triple NANP repeats. Recombinant virus (17D/8) expressing this insertion flanked by two glycine residues at each end, is specifically neutralized by a monoclonal antibody to the model epitope. Furthermore, mouse antibodies raised to the recombinant virus recognize the parasite protein in an ELISA assay. Serial passage analysis confirmed the genetic stability of the insertion made in the viral genome and the resulting 17D/8 virus is significantly more attenuated in mouse neurovirulence tests than the 17DD vaccine. the fg loop belongs to the dimerization domain of the E protein and lies at the interface between monomers. This domain undergoes a low pH transition, which is related to the fusion of the viral envelope to the endosome membrane. It is conceivable that a slower rate of fusion, resulting from the insertion close to the dimer interface, may delay the onset of virus production and thereby lead to a milder infection of the host. This would account for the more attenuated phenotype of the recombinant virus in the mouse model and tower extent of replication in cultured cells. the vectorial capacity of the yellow fever virus is being further explored for the expression and presentation of other epitopes, including those mediating T-cell responses. (C) 2002 Academic Press.
Palavra-chave yellow fever 17D virus
E protein structure
foreign epitope expression
malaria vaccine
Idioma Inglês
Data de publicação 2002-01-25
Publicado em Journal of Molecular Biology. London: Academic Press Ltd Elsevier B.V., v. 315, n. 4, p. 873-885, 2002.
ISSN 0022-2836 (Sherpa/Romeo, fator de impacto)
Publicador Elsevier B.V.
Extensão 873-885
Fonte http://dx.doi.org/10.1006/jmbi.2001.5258
Direito de acesso Acesso restrito
Tipo Artigo
Web of Science WOS:000173836800031
Endereço permanente http://repositorio.unifesp.br/handle/11600/26734

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