Structural mapping of key epitopes on the envelope of dengue virus with regard to neutralization and antibody-dependent enhancement

• Grant number: 14/00684-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: May 01, 2014
• End date: August 31, 2014
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Luis Carlos de Souza Ferreira
• Grantee: Jaime Henrique Amorim Santos
• Supervisor: Richard J. Kuhn
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Purdue University, United States
• Associated to the scholarship: 12/51204-2 - A new way for the rational pursuit of an effective vaccine against dengue, BP.PD

Abstract

The results of the first stage of our research show that mice immunized with the domain III of the envelope glycoprotein and challenged with a lethal dose of dengue virus (same serotype with regard to the protein), in contrast to what we were expecting, died earlier than the non-immunized animals (five experiments). Animals immunized with the domain III antigen developed higher viral loads and pathological signs in a faster way than non-immunized mice. Furthermore, we observed that anti-domain III antibodies, including those purified from protective sera obtained after immunization of animals with inactivated dengue virus particles (those protected to the challenge) enhanced viral infectivity on mammalian cells expressing Fc-³ receptors. We also observed that fractions from the same protective sera, which are specific for domains I and/or II, did not permit virus multiplication in these cells. Currently, we are verifying whether these phenomena observed in mice will be reproduced with human sera. Our first results show that purified human anti-domain III antibodies deliver dengue virus to Fc-gamma receptors-bearing cells and increase dengue virus infectivity. In the next stage of the research we aim to study more deeply the structural epitopes which are target for neutralizing or infection enhancing antibodies. These interactions will be determined by cryo-electron microscopy in a collaborative work with Dr. Kuhn, from Purdue University, USA. The knowledge to be disclosed after carrying out this research will significantly improve the understanding of dengue virus immunopathogenesis and may contribute to the rational development of effective anti-dengue fever vaccines. (AU)