Mecanismos de proteção versus doença na resposta do hospedeiro frente à infecção pelo Dengue vírus em camundongos

Detalhes bibliográficos
Ano de defesa: 2013
Autor(a) principal: Vivian Vasconcelos Costa
Orientador(a): Não Informado pela instituição
Banca de defesa: Não Informado pela instituição
Tipo de documento: Tese
Tipo de acesso: Acesso aberto
Idioma: por
Instituição de defesa: Universidade Federal de Minas Gerais
UFMG
Programa de Pós-Graduação: Não Informado pela instituição
Departamento: Não Informado pela instituição
País: Não Informado pela instituição
Palavras-chave em Português:
Link de acesso: http://hdl.handle.net/1843/BUBD-9BPFPE
Resumo: The host immune response against DENV infection may exert both protective and deleterious effects. Identifying which mediators are associated with each of these conditions may represent a new therapeutic opportunity for the treatment of DHF/DSS. The aim of this study was to investigate some mechanisms associated with protection ordevelopment of severe disease during infection of mice with DENV and also, to identify potential therapeutic targets that could interfere with the course of events associated with the more severe disease manifestation. More specifically, we developed a new model of primary infection with a DENV-3 strain that emulate many of the aspects seen in human disease. Still, we validated this model by studying the role of some mediators known to be associated with host protection against DENV: IL-12/IL-18, IFN- and NOS2 pathway and type I IFNs. We then evaluated the deleterious role associated with activation of bradykinin B2 receptor during the course of primary infection with DENV. The activation of this receptor resulted in severe disease manifestation and increased viral replication, which was pivotal for the elevated mortality rates found in infected mice. We also demonstrated that the humoral immune responses unleashed during DENV infections may play a dual role depending on the context studied. Hence, our data show that B cells are essential for host protection during primary DENV infection; however, in a situation that mimics a secondary infection, sub-neutralizing anti-denguespecific antibodies was associated with exacerbation of disease, via subversion of early host innate antiviral responses and consequent increase in viral replication. In agreement with these findings, administration of a pool of human antibodies containing nonneutralizing DENV doses also resulted in higher mortality rates and more severe disease manifestation after infection with DENV. Finally, we demonstrate that administration of IVIGs at high doses resulted in improvement in all disease parameters without interfering with viral replication in a manner dependent on the production of IL-33. We therefore conclude that interfering with the immune-inflammatory pathways associated with disease evolution may represent potential therapeutic targets for the treatment of DHF/DSS without any loss in control of the infection by the host.