Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2011 |
| Outros Autores: | , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/8684 |
Resumo: | Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil/University of Massachusetts. Medical School. Department of Medicine. Division of Infectious Diseases and Immunology. Worcester, MA |
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Franklin, Bernardo SimõesIshizaka, Sally T.Lamphier, MarcGusovsky, FabianHansen, HansRose, JeffreyZheng, WanjunAtaíde, Marco AntônioOliveira, Rosane Barbosa deGolenbock, Douglas TaylorGazzinelli, Ricardo Tostes2014-10-28T17:13:42Z2014-10-28T17:13:42Z2011FRANKLIN, Bernardo Simões et al. Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria. P NATL ACAD SCI USA, 108(9): 3689-3694, 2011.0027-8424https://www.arca.fiocruz.br/handle/icict/8684engAcademy of Sciences of the United States of AmericaTherapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malariainfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil/University of Massachusetts. Medical School. Department of Medicine. Division of Infectious Diseases and Immunology. Worcester, MAEisai Research Institute. Andover, MAEisai Research Institute. Andover, MAEisai Research Institute. Andover, MAEisai Research Institute. Andover, MAEisai Research Institute. Andover, MAEisai Research Institute. Andover, MAFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil/Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil/Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil/Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquimica e Imunologia. Belo Horizonte, MG, BrazilExcessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.Immunotherapyinnate immunitynucleic acid recognitioninflammationinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-81914https://www.arca.fiocruz.br/bitstream/icict/8684/1/license.txt7d48279ffeed55da8dfe2f8e81f3b81fMD51ORIGINALTherapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria.pdfTherapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria.pdfapplication/pdf1304082https://www.arca.fiocruz.br/bitstream/icict/8684/2/Therapeutical%20targeting%20of%20nucleic%20acid-sensing%20Toll-like%20receptors%20prevents%20experimental%20cerebral%20malaria.pdf32809b05c1e6bbae808d147ce8bcc16bMD52TEXTTherapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria.pdf.txtTherapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria.pdf.txtExtracted texttext/plain41363https://www.arca.fiocruz.br/bitstream/icict/8684/3/Therapeutical%20targeting%20of%20nucleic%20acid-sensing%20Toll-like%20receptors%20prevents%20experimental%20cerebral%20malaria.pdf.txtb85f59207135f0b68ca3389da92e3ad9MD53icict/86842019-06-19 10:12:16.521oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352019-06-19T13:12:16Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false |
| dc.title.pt_BR.fl_str_mv |
Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria |
| title |
Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria |
| spellingShingle |
Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria Franklin, Bernardo Simões Immunotherapy innate immunity nucleic acid recognition inflammation |
| title_short |
Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria |
| title_full |
Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria |
| title_fullStr |
Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria |
| title_full_unstemmed |
Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria |
| title_sort |
Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria |
| author |
Franklin, Bernardo Simões |
| author_facet |
Franklin, Bernardo Simões Ishizaka, Sally T. Lamphier, Marc Gusovsky, Fabian Hansen, Hans Rose, Jeffrey Zheng, Wanjun Ataíde, Marco Antônio Oliveira, Rosane Barbosa de Golenbock, Douglas Taylor Gazzinelli, Ricardo Tostes |
| author_role |
author |
| author2 |
Ishizaka, Sally T. Lamphier, Marc Gusovsky, Fabian Hansen, Hans Rose, Jeffrey Zheng, Wanjun Ataíde, Marco Antônio Oliveira, Rosane Barbosa de Golenbock, Douglas Taylor Gazzinelli, Ricardo Tostes |
| author2_role |
author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Franklin, Bernardo Simões Ishizaka, Sally T. Lamphier, Marc Gusovsky, Fabian Hansen, Hans Rose, Jeffrey Zheng, Wanjun Ataíde, Marco Antônio Oliveira, Rosane Barbosa de Golenbock, Douglas Taylor Gazzinelli, Ricardo Tostes |
| dc.subject.en.pt_BR.fl_str_mv |
Immunotherapy innate immunity nucleic acid recognition inflammation |
| topic |
Immunotherapy innate immunity nucleic acid recognition inflammation |
| description |
Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Imunopatologia. Belo Horizonte, MG, Brazil/University of Massachusetts. Medical School. Department of Medicine. Division of Infectious Diseases and Immunology. Worcester, MA |
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2011 |
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2011 |
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2014-10-28T17:13:42Z |
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2014-10-28T17:13:42Z |
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FRANKLIN, Bernardo Simões et al. Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria. P NATL ACAD SCI USA, 108(9): 3689-3694, 2011. |
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FRANKLIN, Bernardo Simões et al. Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria. P NATL ACAD SCI USA, 108(9): 3689-3694, 2011. 0027-8424 |
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