Modelagem da resposta do hospedeiro ao vírus da dengue e reforço dependente de anticorpos

Author(s)

Miller Orlando Cerón Gómez

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Matemática, Estatística e Computação Científica
• Defense date: 2016-11-17

Examining board members

Hyun Mo Yang; José Luiz Boldrini; María de Lourdes Esteva Peralta; André Ricardo Ribas de Freitas; Gustavo Antonio Olivera Botello

• Advisor: Hyun Mo Yang

Abstract

For many years, the four serotypes of dengue virus have caused asymptomatic to severe and potentially fatal dengue disease in millions of individuals each year. The first dengue infection provides a protection for life against reinfection with the same serotype, but only partial protection against other serotypes. It is believed that existing antibodies against one serotype may increase the severity of the disease, a phenomenon known as \textit{antibody dependent enhancement}. In this thesis, we focus on the mathematical treatment of the interaction between the immune system and dengue virus. First, we develop a mathematical model of the adaptive immune response to dengue virus in the primary infection, in which it is considered that the differentiation of the helper cell mediates the activation of the cellular and humoral immune response. We conclude that the dengue virus is effectively eliminated by the cellular immune response if there exists an intense proliferation of cytotoxic cells. By contrast, in a weak proliferation, the dengue virus is removed by a potent proliferation of activated B cells and/or the inhibition of the activation of Th1 helper cells. Further, the simulations with clinical data demonstrate that cytotoxic activity is inhibited at the beginning of infection, whereas the activated B cells perform the first immune response, which could be a dengue virus strategy for spreading throughout the body. Second, we formulate a mathematical model to explore the antibody-dependent enhancement of dengue disease. We found a threshold for the proliferation parameter of B memory cells. We can see that above this threshold, the high proliferation of non-neutralizing antibodies increases the possibility that antibody-antigen complex will form. Consequently, opsonization by immune cells would become more likely, whereas those below this threshold or the viral particles are either eliminated or reach the minimum level. Finally, we use a Lyapunov direct method to study the global stability of a model of virus dynamics while considering the humoral and cellular immune responses. We found that if the net number of viruses is less than or equal to one, the virus-free equilibrium is globally asymptotically stable. By contrast, the global stability of virus-presence equilibrium is established if the viral entrance rate in the target cells is less than or equal to one (AU)

• FAPESP's process: 13/17264-0 - Modeling the Host Response to Dengue Virus and Antibody Dependent Enhancement
• Grantee: Miller Orlando Cerón Gómez
• Support Opportunities: Scholarships in Brazil - Doctorate