| spelling |
Ricardo Tostes Gazzinellihttp://lattes.cnpq.br/9148354106985023Fabíola Mara RibeiroAristóbolo Mendes da Silvahttp://lattes.cnpq.br/8112421831382040Marco Antônio Ataíde Silva2020-12-09T23:31:17Z2020-12-09T23:31:17Z2011-08-19http://hdl.handle.net/1843/34492Anualmente a infecção por Plasmodium causa a morte de aproximadamente 800.000 indivíduos em todo mundo. Anos de estudos relacionados a patogênese da malária culminaram para o seguinte consenso: a malária é uma doença altamente inflamatória sendo as manifestações clínicas relacionadas com a produção exagerada de mediadores pró-inflamatórios. Nesse trabalho foi demonstrado a presença de dímeros de ASC em amostras de PBMCs, além da caspase-1 ativa em monócitos de pacientes infectados por P.vivax, sendo esses componentes constituintes dos inflamosomos, uma plataforma multiproteica de grande potencial inflamatório. Além disso, foi observado a liberação de altos níveis de IL-1β por PBMCs estimulados com LPS. Foi demonstrado também que caspase-1 é ativada em macrófagos e em células dendríticas durante a malária murina, sendo esse fenômeno dependente dos receptores citosólicos NLRP3 e NLRP12. Normalmente a infecção causada por P.chabaudi, um modelo de malária murina, é resolvida em quatro semanas. No entanto, quando foi administrado baixas doses de LPS durante a fase aguda da doença, níveis elevados de IL-1β e TNFα foram secretados culminando na morte do hospedeiro. Parte dessa susceptibilidade está relacionada com alta produção de IL-1β, um vez que animais IL-1R nocautes são parcialmente resistentes a esse choque. Ademais, foi demonstrado que MyD88, ASC, IFN-γ e TNFR1 controlam esses eventos. Os resultados aqui descritos permitem concluir que a plataforma conhecida como inflamosomo está montada e pronta para gerar altos níveis de IL-1β durante a malária, se um indutor de pro-IL-1β, como por exemplo agonistas de TLRs estiverem disponíveis.Malaria is a major cause of death worldwide infecting around half-billion people annualy. Years of studies on malaria pathogenesis has funneled into consent: malaria is a highly pro-inflammatory disease where clinical manifestations are directly correlated with the induction of high levels of pro-inflammatory mediators. Here we demonstrated a pre-formed ASC dimers and active caspase-1 in monocytes from P.vivax infected patients. Furthermore was observed immediate release of IL-1β by peripheral blood mononuclear cells stimulated with LPS. Additionally we show a new feature of malaria pathogenesis with deleterious consequences even for the non-lethal murine model, Plasmodium chabaudi. We report that caspase 1 is persistently active in macrophages and dendritic cells during acute murine malaria, being this phenomenon NLRP3 and NLRP12 inflammasome-dependent. Usually, P.chabaudi infection resolves at fourth week, but challenging of acute infected mice with low doses of LPS resulted in alarming levels of IL-1β and TNFα, culminating in septic shock-like sydrome and ultimately death. Susceptibility of mice to low LPS doses was associated with a high background of caspase 1 activation and release of IL-1β. We have shown that MyD88, ASC, IFN-γ and TNFR1 signaling controls these events. Together, our results show that the inflammasomes platform is fully assembled and ready to generate high IL-1β levels if an inducer of pro-IL1β, such as TLR agonists, is present during malaria infection.Outra AgênciaporUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em Bioquímica e ImunologiaUFMGBrasilICB - DEPARTAMENTO DE BIOQUÍMICA E IMUNOLOGIAhttp://creativecommons.org/licenses/by-nc-nd/3.0/pt/info:eu-repo/semantics/openAccessCaspase 1Interleucina-1betaMaláriaInflamassomosInflamosomoCaspase-1Interleucina 1 betaMaláriaAtivação de caspase-1 durante a infecção por Plasmodium: avaliação dos componentes envolvidos e implicações na patogênese da Malária.info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALDissertação MESTRADO_Marco A Ataide Silva .pdfDissertação MESTRADO_Marco A Ataide Silva .pdfapplication/pdf15751833https://repositorio.ufmg.br/bitstream/1843/34492/1/Disserta%c3%a7%c3%a3o%20MESTRADO_Marco%20A%20Ataide%20Silva%20.pdfb099c30c2d1b41d53cbbecfb2cde5574MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8811https://repositorio.ufmg.br/bitstream/1843/34492/2/license_rdfcfd6801dba008cb6adbd9838b81582abMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82119https://repositorio.ufmg.br/bitstream/1843/34492/3/license.txt34badce4be7e31e3adb4575ae96af679MD531843/344922020-12-09 20:31:17.253oai:repositorio.ufmg.br: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Repositório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2020-12-09T23:31:17Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
|