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Lis Ribeiro do Valle Antonellihttp://lattes.cnpq.br/4929168581709218Ricardo Tostes Gazzinellihttp://lattes.cnpq.br/9148354106985023Leda Quercia VieiraHelton da Costa SantiagoLuíz Carlos Crocco AfonsoJosé Carlos Farias Alves Filhohttp://lattes.cnpq.br/3544500303769821Suelen Queiroz Diniz2022-02-07T18:14:52Z2022-02-07T18:14:52Z2020-06-01http://hdl.handle.net/1843/39290Em grande parte das infecções parasitárias, existe uma relação dinâmica entre o agente etiológico e o sistema imunológico do hospedeiro, cujo equilíbrio, se alterado, pode influenciar o prognóstico da doença. Na infecção malárica, o Plasmodium spp. desencadeia a produção de altos níveis de citocinas inflamatórias que são essenciais para o controle do parasito, mas também são responsáveis pelos sintomas da doença. Nosso grupo demonstrou que os monócitos desempenham um papel importante na proteção contra o P. vivax, constituindo uma importante fonte de citocinas inflamatórias e de espécies reativas de oxigênio. A fim de modular a inflamação, citocinas anti-inflamatórias também são produzidas. Estudos sugerem que as diferentes apresentações clínicas dos pacientes com malária causada pelo P. vivax estão fortemente associadas a um desequilíbrio no balanço entre citocinas inflamatórias e anti-inflamatórias. Apesas dos avanços no entendimento acerca dos mecanismos protetores e imunopatológicos, pouco é sabido em relação a manutenção desse equilíbrio durante a malária. O presente estudo demonstrou que durante a infecção pelo P. vivax, há uma reprogramação no metabolismo dos monócitos e a mitocôndria desempenha um papel central nesse fenômeno. Essa transição consiste em um aumento da captação de glicose, bem como na produção de ATP via glicólise. Essas alterações estão associadas a aumento no potencial de membrana mitocondrial, favorecendo a produção de mROS. Esse mecanismo pode estar envolvido no controle do parasito, visto que a mitocôndria é capaz de migrar para o fagolisossomo contendo o Pv-RET e produzir mROS. Por outro lado, os monócitos também atuam na modulação dessa resposta inflamatória. Essas células expressam níveis mais altos de ectonucleotidases em relação aos demais leucócitos, indicando um importante papel na modulação do ATP extracelular e consequentemente, na produção de adenosina. Apesar dos níveis plasmáticos de adenosina terem diminuído em pacientes com malária aguda causada pelo P. vivax, os mesmos pacientes exibem uma expressão aumentada de receptores purinérgicos P1 nas subpopulações de monócitos. Ademais, a adenosina aumenta a produção de IL-10 e diminui a de TNF pelos monócitos, sendo esse efeito completamente abolido com o bloqueio do receptor A2A. Em conjunto, nossos dados demonstram que os monócitos têm um papel duplo durante a malária causada pelo P. vivax, tentando simultaneamente controlar a infecção e a potencial resposta inflamatória deletéria.In most parasitic infections, there is a relationship between the etiologic agent and the host's immune system, whose balance, if altered, can influence the host’s susceptibility and, therefore, the prognosis of the disease. During malaria, Plasmodium spp. triggers the production of high levels of inflammatory cytokines that are both essential for the control of the parasite and responsible for the symptoms observed during the disease. Our group demonstrated that monocytes play an important role in host defense against Plasmodium vivax infection and represent the main source of inflammatory cytokines and reactive oxygen species. In order to modulate inflammation, anti-inflammatory cytokines, such as IL-10, are also produced. Studies suggested that different clinical presentations of malaria are strongly associated with an imbalance in inflammatory and anti-inflammatory cytokines production. Based on that, despite advances in our understanding of the involvement of protective and immunopathological immunity, little is known about maintaining this balance during malaria. The present study demonstrates that during P. vivax infection monocyte metabolism is altered with mitochondria playing a major function in this switch. This transition involves a reprograming in monocyte metabolism in which the cells increase glucose uptake and produce ATP via glycolysis instead of via oxidative phosphorylation (OXPHOS). Morevover, the above changes are associated with altered mitochondrial membrane potential leading to an increase in mROS instead of ATP production, which can be involved in parasite control since these organells are able to migrate to the phagolysosome containing the Pv-RET and produced mROS. On the other hand, monocytes also participate in the modulation of this inflammatory response during malaria. They express higher levels of ectonucleotidases than other leukocytes, indicating their important role in extracellular ATP modulation and consequently in adenosine production. Despite plasmatic levels of adenosine were decreased in patients experiencing acute malaria caused by P. vivax, the same patients display an increased expression of P1 purinergic receptors on monocyte subsets. In addition, adenosine increases IL-10 and decreases TNF production by monocytes. Importantly, this effect was completely abolished with the blockage of A2a receptor. All together our data show that monocytes have a dual role during malaria caused by P. vivax, simultaneously attempting to control the infection and the potential deleterious inflammatory response.porUniversidade Federal de Minas GeraisPrograma de Pós-Graduação em Bioquímica e ImunologiaUFMGBrasilICB - DEPARTAMENTO DE BIOQUÍMICA E IMUNOLOGIABioquímica e imunologiaMaláriaPlasmodium vivaxMonócitosMetabolismoMaláriaMonócitosMitocôndriasAdenosinaMetabolismoMecanismos efetores de monócitos na malária humana causada pelo Plasmodium vivaxinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALSD Tese completa - final.pdfSD Tese completa - final.pdfapplication/pdf13013738https://repositorio.ufmg.br/bitstream/1843/39290/3/SD%20Tese%20completa%20-%20final.pdf43904756e09df334901e8ed3f451bbcfMD53LICENSElicense.txtlicense.txttext/plain; charset=utf-82118https://repositorio.ufmg.br/bitstream/1843/39290/4/license.txtcda590c95a0b51b4d15f60c9642ca272MD541843/392902022-02-07 15:14:52.817oai:repositorio.ufmg.br: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ório InstitucionalPUBhttps://repositorio.ufmg.br/oaiopendoar:2022-02-07T18:14:52Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false
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