Identification of epitopes present in the e protein of dengue virus type 2 (DENV2) capable of generating neutralizing antibodies without causing exacerbation of viral replication

• Grant number: 14/04303-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): August 01, 2014
• Effective date (End): July 31, 2018
• Field of knowledge: Biological Sciences - Parasitology
• Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Luis Carlos de Souza Ferreira
• Grantee: Denicar Lina Nascimento Fabris
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The dengue, disease caused by one of four serotypes of dengue (DENV 1-4), infection is the main arbovirus that currently affects humans. Though some 390 million people are infected annually by one of the types of DENV, there aren't vaccines or therapies to control the disease. A major difficulty for developing a vaccine is the lack of knowledge about the major target for neutralizing antibody epitopes in the viral particle. It was believed that the domain III of the envelope glycoprotein (EDIII) of DENV concentrate the main targets for neutralizing antibodies, but results generated during the master's student revealed a different reality. EDIII homotypic antibodies , although capable of preventing infection of cells devoid of receptors type the Fc- ³ for DENV2, direct viral particles to cells that express these receptors promoting increased virus replication under both in vitro and in vivo. Furthermore, it was demonstrated that antibodies that protect cells expressing Fc-³ receptors are directed against other domains, linear and conformational epitopes present on the surface of the viral particle. The objective of this project is therefore to identify and map the target epitopes, whether linear or conformational, neutralizing antibodies to not promote increased viral replication, particularly during the infectious process in vivo. Linear epitopes will be identified using ELISA against peptides derived from different domains of the E protein while conformational epitopes will be identified by cryo-electron microscopy. Recombinant antigens are generated from the results obtained and tested in vivo in an experimental model based on a strain of DENV2 able to infect and kill immunocompetent mice. The knowledge generated from this research will allow more rational approaches are applied to the development of vaccines against dengue. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PEREIRA, LENNON RAMOS; VICENTIN, ELAINE CRISTINA MATOS; PEREIRA, SARA ARAUJO; MAEDA, DENICAR LINA NASCIMENTO FABRIS; ALVES, RUBENS PRINCE DOS SANTOS; ANDREATA-SANTOS, ROBERT; SOUSA, FRANCIELLE TRAMONTINI GOMES DE; YAMAMOTO, MARCIO MASSAO; CASTRO-AMARANTE, MARIA FERNANDA; FAVARO, MARIANNA TEIXEIRA DE PINHO; et al. Intradermal Delivery of Dendritic Cell-Targeting Chimeric mAbs Genetically Fused to Type 2 Dengue Virus Nonstructural Protein 1. VACCINES, v. 8, n. 4, DEC 2020. (13/26942-2, 14/04303-0, 16/05570-8, 13/01702-9, 13/11442-4, 14/17595-0, 13/01690-0)