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Hemozoin as an immune stimulant of the mosquito Anopheles gambiae response against the malaria parasite
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Hemozoína, um metabolito produzido por Plasmodium spp., tem surgido como um potente estimulador, activando o sistema imunitário do hospedeiro e levando à produção de citocinas e quimiocinas em tecidos de mamíferos. Neste estudo, desvendamos o papel deste subproduto do parasita como estimulador da imunidade de Anopheles gambiae em
resposta à infecção por Plasmodium berghei. A malária é uma doença infecciosa de distribuição mundial, causada por parasitas do género Plasmodium e transmitida pelas fêmeas de mosquitos do género Anopheles. A resposta imunitária do mosquito vector da malária contra o parasita envolve várias vias metabólicas que não se encontram ainda bem caracterizadas. Resultados laboratoriais revelaram que a hemozoína activa a expressão de
vários genes da imunidade, incluindo péptidos anti-microbianos e factores anti-Plasmodium. Destaca-se a indução, após estimulação com hemozoína, da forma larga (REL2-F) do factor de transcrição REL2, da via Immune deficiency (Imd). Estes resultados foram confirmados pela estimulação de tecidos e células de Anopheles gambiae com hemozoína sintética e silenciamento do gene que codifica REL2-F e do gene que codifica o seu regulador negativo Caspar. Neste trabalho, mostrou-se pela primeira vez o impacto do tratamento com hemozoína na infecção por Plasmodium: a hemozoína reduz eficientemente tanto a taxa como a intensidade da infecção no mosquito. Propomos, assim, que a hemozoína estimula a imunidade inata de Anopheles, activando a expressão de genes efectores que tornam o mosquito mais resistente ao Plasmodium, e que esta activação é mediada por REL2.
Após identificação de um conjunto de genes associados à imunidade induzidos pela hemozoína, e de acordo com as propriedades da via Imd/REL2 sugeridas pelos resultados obtidos, construímos uma linha de mosquitos Anopheles gambiae geneticamente modificados, através da sobreexpressão do gene anti-plasmódico FBN9 (fibrinogen
immunolectin 9), sob regulação de Vitellogenin 1, um promotor específico do corpo gordo.
The Plasmodiummetabolite hemozoin has emerged as a potent immunostimulator, targeting the host immune system and activating the production of cytokines and chemokines in mammalian tissues. In this study, we disclose the role of this parasite’s byproduct as stimulator of Anopheles gambiaeimmunity to Plasmodium berghei. Malaria is a worldwide infectious disease caused by Plasmodiumparasites and transmitted by female Anophelesmosquitoes. The malaria vector mosquitoAnophelesimmune response to the parasite involves several pathways which are not yet well characterized. High throughput analyses revealed that hemozoin activates the expression of several immunity genes, including antimicrobial peptides (AMPs) and anti-Plasmodiumfactors. Importantly, we found that the Immune deficiency (Imd) pathway transcription factor REL2, in its full-length form REL2-F, was induced upon hemozoin treatment. These findings were confirmed by stimulation of Anopheles gambiaetissues and cells with synthetic hemozoin and silencing of REL2-F and its negative regulator Caspar. Notably, we have for the first time shown the impact of hemozoin treatment on Plasmodiuminfection, effectivelyreducing both rate and intensity of the infection. We propose that hemozoin boosts the innate immunity in Anopheles, activating key effector genes that turn the mosquito more resistantto Plasmodium, and this activation is REL2-mediated. Following identification ofa set of key immunity genes induced by hemozoin and encouraged by the properties of the Imd/REL2 pathway suggested by the obtained results,we have successfully engineered a genetically modified Anopheles gambiaeline, by overexpressionof FBN9(fibrinogen immunolectin 9) antiparasitic gene under regulation of the fat body-specific Vitellogenin 1 promoter.
The Plasmodiummetabolite hemozoin has emerged as a potent immunostimulator, targeting the host immune system and activating the production of cytokines and chemokines in mammalian tissues. In this study, we disclose the role of this parasite’s byproduct as stimulator of Anopheles gambiaeimmunity to Plasmodium berghei. Malaria is a worldwide infectious disease caused by Plasmodiumparasites and transmitted by female Anophelesmosquitoes. The malaria vector mosquitoAnophelesimmune response to the parasite involves several pathways which are not yet well characterized. High throughput analyses revealed that hemozoin activates the expression of several immunity genes, including antimicrobial peptides (AMPs) and anti-Plasmodiumfactors. Importantly, we found that the Immune deficiency (Imd) pathway transcription factor REL2, in its full-length form REL2-F, was induced upon hemozoin treatment. These findings were confirmed by stimulation of Anopheles gambiaetissues and cells with synthetic hemozoin and silencing of REL2-F and its negative regulator Caspar. Notably, we have for the first time shown the impact of hemozoin treatment on Plasmodiuminfection, effectivelyreducing both rate and intensity of the infection. We propose that hemozoin boosts the innate immunity in Anopheles, activating key effector genes that turn the mosquito more resistantto Plasmodium, and this activation is REL2-mediated. Following identification ofa set of key immunity genes induced by hemozoin and encouraged by the properties of the Imd/REL2 pathway suggested by the obtained results,we have successfully engineered a genetically modified Anopheles gambiaeline, by overexpressionof FBN9(fibrinogen immunolectin 9) antiparasitic gene under regulation of the fat body-specific Vitellogenin 1 promoter.
Descrição
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Parasitologia médica Malária Parasita Mosquito anopheles gambiae Biologia molecular
Contexto Educativo
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Instituto de Higiene e Medicina Tropical