O papel do interferon do tipo I e sua sinalização na resposta imune inata contra a infecção pela Brucella abortus

• Ano de defesa: 2010
• Autor(a) principal: Leonardo Augusto de Almeida
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; UFMG
• Palavras-chave em Português: Bioquímica e imunologia; Bioquímica; Brucella abortus; Imunidade natural
• Link de acesso: http://hdl.handle.net/1843/BUOS-8RGH2T

Brucella abortus is a Gram-negative bacterium, facultative intracellular pathogen, which causes undulant fever in humans and infertility among animals, resulting in serious economic losses. Brucella recognition mediated by PRRs, such as TLR2, TLR4 or TLR9 via MyD88 is an important step to establish immune responses against this organism and an efficient bacterial clearance. Based on recent studies that have revealed the involvement of IFN-R signaling pathway in bacterial infection, we decided to study the role of type I interferon system activation in the innate immune response against B. abortus. Firstly, we determined that B. abortus induced IFN- and IFN- production, being IFN- more prominent. To access the role of IFN-R signaling, IFN-R-/- mice were infected and the number of viable bacteria recovery from spleen showed to be lower when compared to wild type mice. IFN-R-/- showed a greater increase in IFN- and NO level in culture cells when stimulated with B. abortus and a lower apoptotic index in spleen from these mice. Related to this phenotype, TRAIL expression showed to be decreased in BMMØs from IFN-R-/- mice and STAT1-Tyr701 phosphorilation was demonstrated inexistent in these cells. To understand the type I interferon activation by B. abortus, the IFN- expression was measured in BMMØs from TLR2-/-, TLR4-/-, TLR9-/- or TRIF-/-. It was demonstrated that IFN- expression shows no difference in these mice when compared to control mice cells. However, IFN- expression requires MyD88- signaling. Regarding IRF-3, siRNA demonstrated that IFN- expression induced by B. abortus is IRF-3-dependent. Additionally, to determine if B. abortus DNA is capable to induce IFN-, BMMØs were stimulated with either live bacteria or purified DNA. The results obtained here suggested that both live bacteria and their purified DNA were capable to induce IFN- in a TLR2, TLR4 or TLR9 receptors independent manner but dependent on MyD88 and IRF-3. In summary, this study suggests that B. abortus induces IFN- production and apoptosis to continue the infectious process in the host. Apoptosis culminate not only with membrane cellular fragmentation leading the B. abortus release where these released bacteria are able to infect new adjacent host cells, but also the apoptotic bodies can be a vehicle to infect, in a silencing way, other host cells