Study of protective mechanisms induced by vaccination of mice with fusion antibodies that target the dengue virus proteins to dendritic cells

• Grant number: 13/11442-4
• Support Opportunities: Regular Research Grants
• Duration: September 01, 2013 - February 29, 2016
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Silvia Beatriz Boscardin
• Grantee: Silvia Beatriz Boscardin
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Luis Carlos de Souza Ferreira

Abstract

Dendritic cells (DCs) are critical for the interaction between the innate and adaptive immune systems, phagocytosing antigens and presenting them to lymphocytes, being able to induce tolerance or strong adaptive responses against pathogens. This property makes these cells interesting targets for the development of new vaccine strategies. Over the past 4 years, we established for the first time in Brazil a strategy that targets antigens directly to DCs in vivo. This strategy consists in the use of a monoclonal antibody (mAb) against a receptor present on the surface of DC in fusion with the antigen of interest. The administration of low doses of the fusion antibody, in the presence of DC maturation stimuli, is able to activate antigen-specific T cells and induce production of high antibody titers against the antigen of interest. Currently, DCs comprise a very heterogeneous cell population. Some surface markers define subpopulations that have different abilities to process and present antigens, and this differential capacity is responsible for the activation of specific populations of T cells. In a previous project (see article submitted to "other documents" in SAGE), we were able to direct the non-structural protein 1 (NS1) of dengue virus to two DC subpopulations. Antigen targeting to the population expressing the DEC205 endocytic receptor induced strong anti-NS1 immune response and was able to protect animals against a challenge with DENV-2, when we used poly I:C as adjuvant. This response appears to be mediated mainly by T lymphocytes, but the participation of antibodies in the pathogenesis or protection also needs to be studied in greater detail. In an attempt to better study the T lymphocyte mediated response, we intend to map the epitope(s) in the NS1 protein that is(are) responsible for the generation of specific and protective CD4+ T cells in our model. The role of anti-NS1 antibodies in protection or patogenesis of the disease will be studied using passive transfer assays and through the analysis of platelet function in the immunized animals. Besides the NS1 protein, the dengue virus envelope (E) protein is also the target of the immune system and antibodies that recognize it may have neutralizing activity. Moreover, there are reports that such antibodies could also have a deleterious effect and contribute to disease pathogenesis. To study the role of anti-E antibodies in our targeting model, we intend to generate E protein fusion mAbs (±DEC or ±DCIR2) and evaluate each anti-E immune response component in protection and/or disease pathogenesis. In summary, in this project we intend to analyze the role of cellular and humoral immune responses in protection or in pathogenesis of dengue when the NS1 and E proteins are directed to two distinct DCs populations. (AU)

Scientific publications

(10)

(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)

AMORIM, KELLY N. S.; RAMPAZO, ELINE V.; ANTONIALLI, RENAN; YAMAMOTO, MARCIO M.; RODRIGUES, MAURICIO M.; SOARES, IRENE S.; BOSCARDIN, SILVIA B.. The presence of T cell epitopes is important for induction of antibody responses against antigens directed to DEC205(+) dendritic cells. SCIENTIFIC REPORTS, v. 6, DEC 21 2016. (13/11442-4, 07/08648-9)

APOSTOLICO, JULIANA DE SOUZA; SANTOS LUNARDELLI, VICTORIA ALVES; YAMAMOTO, MARCIO MASSAO; SANTOS SOUZA, HIGO FERNANDO; CUNHA-NETO, EDECIO; BOSCARDIN, SILVIA BEATRIZ; ROSA, DANIELA SANTORO. Dendritic Cell Targeting Effectively Boosts T Cell Responses Elicited by an HIV Multiepitope DNA Vaccine. FRONTIERS IN IMMUNOLOGY, v. 8, FEB 7 2017. (14/15061-8, 13/11442-4)

AMORIM, KELLY N. S.; CHAGAS, DANIELE C. G.; SULCZEWSKI, FERNANDO B.; BOSCARDIN, SILVIA B.. Dendritic Cells and Their Multiple Roles during Malaria Infection. JOURNAL OF IMMUNOLOGY RESEARCH, v. 2016, p. 11-pg., 2016-01-01. (07/08648-9, 13/11442-4)

APOSTOLICO, JULIANA DE SOUZA; SANTOS LUNARDELLI, VICTORIA ALVES; COIRADA, FERNANDA CAROLINE; BOSCARDIN, SILVIA BEATRIZ; ROSA, DANIELA SANTORO. Adjuvants: Classification, Modus Operandi, and Licensing. JOURNAL OF IMMUNOLOGY RESEARCH, v. 2016, p. 16-pg., 2016-01-01. (13/11442-4, 14/15061-8)

APOSTOLICO, JULIANA DE SOUZA; SANTOS LUNARDELLI, VICTORIA ALVES; COIRADA, FERNANDA CAROLINE; BOSCARDIN, SILVIA BEATRIZ; ROSA, DANIELA SANTORO. Adjuvants: Classification, Modus Operandi, and Licensing. CLINICAL & DEVELOPMENTAL IMMUNOLOGY, 2016. (14/15061-8, 13/11442-4)

AMORIM, KELLY N. S.; CHAGAS, DANIELE C. G.; SULCZEWSKI, FERNANDO B.; BOSCARDIN, SILVIA B.. Dendritic Cells and Their Multiple Roles during Malaria Infection. CLINICAL & DEVELOPMENTAL IMMUNOLOGY, 2016. (13/11442-4, 07/08648-9)

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)

ANTONIALLI, RENAN; SULCZEWSKI, FERNANDO BANDEIRA; DA SILVA AMORIM, KELLY NAZARE; ALMEIDA, BIANCA DA SILVA; FERREIRA, NATALIA SOARES; YAMAMOTO, MARCIO MASSAO; SOARES, IRENE SILVA; DE SOUZA FERREIRA, LUIS CARLOS; ROSA, DANIELA SANTORO; BOSCARDIN, SILVIA BEATRIZ. CpG Oligodeoxinucleotides and Flagellin Modulate the Immune Response to Antigens Targeted to CD8 alpha(+) and CD8 alpha(-) Conventional Dendritic Cell Subsets. FRONTIERS IN IMMUNOLOGY, v. 8, DEC 4 2017. (14/50631-0, 13/11442-4, 15/18874-2)

SANTOS SOUZA, HIGO FERNANDO; ALMEIDA, BIANCA DA SILVA; BOSCARDIN, SILVIA BEATRIZ. Early dengue virus interactions: the role of dendritic cells during infection. VIRUS RESEARCH, v. 223, p. 88-98, SEP 2 2016. (13/11442-4, 14/50631-0)

ZANETI, ARTHUR BARUEL; YAMAMOTO, MARCIO MASSAO; SULCZEWSKI, FERNANDO BANDEIRA; ALMEIDA, BIANCA DA SILVA; SANTOS SOUZA, HIGO FERNANDO; FERREIRA, NATALIA SOARES; NASCIMENTO FABRIS MAEDA, DENICAR LINA; SALES, NATIELY SILVA; ROSA, DANIELA SANTORO; DE SOUZA FERREIRA, LUIS CARLOS; et al. Dendritic Cell Targeting Using a DNA Vaccine Induces Specific Antibodies and CD4(+) T Cells to the Dengue Virus Envelope Protein Domain III. FRONTIERS IN IMMUNOLOGY, v. 10, JAN 29 2019. (16/04477-4, 13/11442-4, 14/50631-0, 14/17595-0, 15/16565-2, 14/15061-8, 15/18874-2)