Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients
Autor(a) principal: | |
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Data de Publicação: | 2018 |
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/28360 |
Resumo: | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratórios e do Sarampo. Rio de Janeiro, RJ, Brazil / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil. |
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Garcia, Cristiana CoutoTavares, Luciana PaduaDias, Ana Carolina FialhoKehdy, Fernanda de Souza GomesAlvarado-Arnez, Lucia ElenaQueiroz Junior, Celso M.Galvão, IzabelaLima, Braulio HenriqueMatos, Aline da RochaGonçalves, Ana Paula de FariaSoriani, Frederico MarianettiMoraes, Milton OzórioMarques, João TrindadeSiqueira, Marilda Agudo Mendonça Teixeira deMachado, Alexandre de Magalhães VieiraSousa, Lirlandia PiresRusso, Remo de CastroTeixeira, Mauro Martins2018-08-24T16:44:27Z2018-08-24T16:44:27Z2018GARCIA, Cristiana Couto et al. Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients. Frontiers in Immunology, v. 9, p. 1-18, 2018.1664-3224https://www.arca.fiocruz.br/handle/icict/2836010.3389/fimmu.2018.00975engFrontiers Media ASCélulas T CD8 +Gravidade da doençaCélulas assassinas naturaisNeutrófilosp38Polimorfismo de nucleotídeo únicoType-I IFNCD8+ T cellsDisease SeverityNatural killer cellsNeutrophilsp38Single-nucleotide polymorphismType-I IFNPhosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patientsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratórios e do Sarampo. Rio de Janeiro, RJ, Brazil / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Fisiologia e Biofísica. Laboratório de Imunologia e Mecânica Pulmonar. Belo Horizonte, MG, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brazil / UNIFRANZ. Coordinación Nacional de Investigación. La Paz, Bolivia.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Morfologia. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil / Universidade de São Paulo. Departamento de Farmacologia. Laboratório de Inflamação e Dor. Universidade de São Paulo. Ribeirão Preto, SP, Brazil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratórios e do Sarampo. Rio de Janeiro, RJ, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil / Fundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Imunologia de Doenças Virais. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Biologia Geral. Belo Horizonte, MG, Brazil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de RNA de Interferência Belo Horizonte, MG, Brazil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratórios e do Sarampo. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Imunologia de Doenças Virais. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil / Universidade Federal de Minas Gerais. Faculdade de Farmácia. Departamento de Análises Clínicas e Toxicológicas. Belo Horizonte, MG, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Fisiologia e Biofísica. Laboratório de Imunologia e Mecânica Pulmonar. Belo Horizonte, MG, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil.Influenza A virus (IAV) infection causes severe pulmonary disease characterized by intense leukocyte infiltration. Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes, involved in cell growth, survival, and migration. Class IB PI3K or phosphatidyl inositol 3 kinase-gamma (PI3Kγ), mainly expressed by leukocytes, is involved in cell migration during inflammation. Here, we investigated the contribution of PI3Kγ for the inflammatory and antiviral responses to IAV. PI3Kγ knockout (KO) mice were highly susceptible to lethality following infection with influenza A/WSN/33 H1N1. In the early time points of infection, infiltration of neutrophils was higher than WT mice whereas type-I and type-III IFN expression and p38 activation were reduced in PI3Kγ KO mice resulting in higher viral loads when compared with WT mice. Blockade of p38 in WT macrophages infected with IAV reduced levels of interferon-stimulated gene 15 protein to those induced in PI3Kγ KO macrophages, suggesting that p38 is downstream of antiviral responses mediated by PI3Kγ. PI3Kγ KO-derived fibroblasts or macrophages showed reduced type-I IFN transcription and altered pro-inflammatory cytokines suggesting a cell autonomous imbalance between inflammatory and antiviral responses. Seven days after IAV infection, there were reduced infiltration of natural killer cells and CD8+ T lymphocytes, increased concentration of inflammatory cytokines in bronchoalveolar fluid, reduced numbers of resolving macrophages, and IL-10 levels in PI3Kγ KO. This imbalanced environment in PI3Kγ KO-infected mice culminated in enhanced lung neutrophil infiltration, reactive oxygen species release, and lung damage that together with the increased viral loads, contributed to higher mortality in PI3Kγ KO mice compared with WT mice. In humans, we tested the genetic association of disease severity in influenza A/H1N1pdm09-infected patients with three potentially functional PIK3CG single-nucleotide polymorphisms (SNPs), rs1129293, rs17847825, and rs2230460. We observed that SNPs rs17847825 and rs2230460 (A and T alleles, respectively) were significantly associated with protection from severe disease using the recessive model in patients infected with influenza A(H1N1)pdm09. Altogether, our results suggest that PI3Kγ is crucial in balancing antiviral and inflammatory responses to IAV infection.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-83082https://www.arca.fiocruz.br/bitstream/icict/28360/1/license.txt9193a7c197bc67acd023525e72a03240MD51ORIGINALPhosphatidyl Inositol 3 Kinase-Gamma Balances.pdfPhosphatidyl Inositol 3 Kinase-Gamma Balances.pdfapplication/pdf10035595https://www.arca.fiocruz.br/bitstream/icict/28360/2/Phosphatidyl%20Inositol%203%20Kinase-Gamma%20Balances.pdf5a61fb2c618990d4314d36db3868ee2eMD52TEXTPhosphatidyl Inositol 3 Kinase-Gamma Balances.pdf.txtPhosphatidyl Inositol 3 Kinase-Gamma Balances.pdf.txtExtracted 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dc.title.pt_BR.fl_str_mv |
Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients |
title |
Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients |
spellingShingle |
Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients Garcia, Cristiana Couto Células T CD8 + Gravidade da doença Células assassinas naturais Neutrófilos p38 Polimorfismo de nucleotídeo único Type-I IFN CD8+ T cells Disease Severity Natural killer cells Neutrophils p38 Single-nucleotide polymorphism Type-I IFN |
title_short |
Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients |
title_full |
Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients |
title_fullStr |
Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients |
title_full_unstemmed |
Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients |
title_sort |
Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients |
author |
Garcia, Cristiana Couto |
author_facet |
Garcia, Cristiana Couto Tavares, Luciana Padua Dias, Ana Carolina Fialho Kehdy, Fernanda de Souza Gomes Alvarado-Arnez, Lucia Elena Queiroz Junior, Celso M. Galvão, Izabela Lima, Braulio Henrique Matos, Aline da Rocha Gonçalves, Ana Paula de Faria Soriani, Frederico Marianetti Moraes, Milton Ozório Marques, João Trindade Siqueira, Marilda Agudo Mendonça Teixeira de Machado, Alexandre de Magalhães Vieira Sousa, Lirlandia Pires Russo, Remo de Castro Teixeira, Mauro Martins |
author_role |
author |
author2 |
Tavares, Luciana Padua Dias, Ana Carolina Fialho Kehdy, Fernanda de Souza Gomes Alvarado-Arnez, Lucia Elena Queiroz Junior, Celso M. Galvão, Izabela Lima, Braulio Henrique Matos, Aline da Rocha Gonçalves, Ana Paula de Faria Soriani, Frederico Marianetti Moraes, Milton Ozório Marques, João Trindade Siqueira, Marilda Agudo Mendonça Teixeira de Machado, Alexandre de Magalhães Vieira Sousa, Lirlandia Pires Russo, Remo de Castro Teixeira, Mauro Martins |
author2_role |
author author author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Garcia, Cristiana Couto Tavares, Luciana Padua Dias, Ana Carolina Fialho Kehdy, Fernanda de Souza Gomes Alvarado-Arnez, Lucia Elena Queiroz Junior, Celso M. Galvão, Izabela Lima, Braulio Henrique Matos, Aline da Rocha Gonçalves, Ana Paula de Faria Soriani, Frederico Marianetti Moraes, Milton Ozório Marques, João Trindade Siqueira, Marilda Agudo Mendonça Teixeira de Machado, Alexandre de Magalhães Vieira Sousa, Lirlandia Pires Russo, Remo de Castro Teixeira, Mauro Martins |
dc.subject.other.pt_BR.fl_str_mv |
Células T CD8 + Gravidade da doença Células assassinas naturais Neutrófilos p38 Polimorfismo de nucleotídeo único Type-I IFN |
topic |
Células T CD8 + Gravidade da doença Células assassinas naturais Neutrófilos p38 Polimorfismo de nucleotídeo único Type-I IFN CD8+ T cells Disease Severity Natural killer cells Neutrophils p38 Single-nucleotide polymorphism Type-I IFN |
dc.subject.en.pt_BR.fl_str_mv |
CD8+ T cells Disease Severity Natural killer cells Neutrophils p38 Single-nucleotide polymorphism Type-I IFN |
description |
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratórios e do Sarampo. Rio de Janeiro, RJ, Brazil / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil. |
publishDate |
2018 |
dc.date.accessioned.fl_str_mv |
2018-08-24T16:44:27Z |
dc.date.available.fl_str_mv |
2018-08-24T16:44:27Z |
dc.date.issued.fl_str_mv |
2018 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
GARCIA, Cristiana Couto et al. Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients. Frontiers in Immunology, v. 9, p. 1-18, 2018. |
dc.identifier.uri.fl_str_mv |
https://www.arca.fiocruz.br/handle/icict/28360 |
dc.identifier.issn.pt_BR.fl_str_mv |
1664-3224 |
dc.identifier.doi.none.fl_str_mv |
10.3389/fimmu.2018.00975 |
identifier_str_mv |
GARCIA, Cristiana Couto et al. Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients. Frontiers in Immunology, v. 9, p. 1-18, 2018. 1664-3224 10.3389/fimmu.2018.00975 |
url |
https://www.arca.fiocruz.br/handle/icict/28360 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Frontiers Media AS |
publisher.none.fl_str_mv |
Frontiers Media AS |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da FIOCRUZ (ARCA) instname:Fundação Oswaldo Cruz (FIOCRUZ) instacron:FIOCRUZ |
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Fundação Oswaldo Cruz (FIOCRUZ) |
instacron_str |
FIOCRUZ |
institution |
FIOCRUZ |
reponame_str |
Repositório Institucional da FIOCRUZ (ARCA) |
collection |
Repositório Institucional da FIOCRUZ (ARCA) |
bitstream.url.fl_str_mv |
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MD5 MD5 MD5 |
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Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ) |
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repositorio.arca@fiocruz.br |
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1813009175070900224 |