Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons

Detalhes bibliográficos
Autor(a) principal: Sousa, Thiago das Chagas
Data de Publicação: 2022
Outros Autores: Martins, Jessica Santa Cruz Carvalho, Miranda, Milene Dias, Garcia, Cristiana Couto, Resende, Paola Cristina, Santos, Cliomar A., Debur, Maria do Carmo, Rodrigues, Rodrigo Ribeiro, Cavalcanti, Andrea Cony, Gregianini, Tatiana Schäffer, Iani, Felipe Campos de Melo, Pereira, Felicidade Mota, Fernandes, Sandra Bianchini, Ferreira, Jessylene de Almeida, Santos, Katia Correa de Oliveira, Motta, Fernando, Brown, David, Almeida, Walquiria Aparecida Ferreira de, Siqueira, Marilda Mendonça, Matos, Aline da Rocha
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/56816
Resumo: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, Brasil.
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spelling Sousa, Thiago das ChagasMartins, Jessica Santa Cruz CarvalhoMiranda, Milene DiasGarcia, Cristiana CoutoResende, Paola CristinaSantos, Cliomar A.Debur, Maria do CarmoRodrigues, Rodrigo RibeiroCavalcanti, Andrea ConyGregianini, Tatiana SchäfferIani, Felipe Campos de MeloPereira, Felicidade MotaFernandes, Sandra BianchiniFerreira, Jessylene de AlmeidaSantos, Katia Correa de OliveiraMotta, FernandoBrown, DavidAlmeida, Walquiria Aparecida Ferreira deSiqueira, Marilda MendonçaMatos, Aline da Rocha2023-02-01T15:28:43Z2023-02-01T15:28:43Z2022SOUSA, Thiago das Chagas et al. Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons. Frontiers in Public Health, 10, 944277, p. 1 - 9, Sept. 2022.2296-2565https://www.arca.fiocruz.br/handle/icict/5681610.3389/fpubh.2022.944277engFrontiers MediaVírus da gripe AInibidores da neuraminidase (NA)OseltamivirBaloxavir marboxiLAdamantanoResistênciaInfluenza A virusNeuraminidase (NA) inhibitorsOseltamivirBaloxavir marboxiLAdamantaneResistanceLow prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasonsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, Brasil.Laboratório Central de Saúde Publica de Sergipe (LACEN-SE). Aracaju, Sergipe, Brasil.Laboratório Central do Estado do Paraná (LACEN-PR). Curitiba, Paraná, Brasil.Laboratório de Saúde Pública do Estado do Espírito Santo, Secretaria de Saúde do Estado do Espírito Santo (LACEN-ES)., Vitória, Espirito Santo, Brasil / Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, Espirito Santo, Brasil.Laboratório Central de Saúde Pública do Rio de Janeiro (LACEN-RJ. Rio de Janeiro, RJ, Brasil.Laboratório Central de Saúde Pública da Secretaria de Saúde do estado do Rio Grande do Sul, (LACEN-RS)/CEVS/SES-RS, Porto Alegre, RS, Brasil.Laboratório Central de Saúde Pública de Minas Gerais (LACEN-MG), Fundação Ezequiel Dias, Belo Horizonte, MG, Brasil.Laboratório Central da Saúde Pública do estado da Bahia (LACEN-BA). Salvador, BA, Brasil.Laboratório Central de Santa Catarina (LACEN-SC), Florianópolis, Santa Catarina, Brasil.Instituto Evandro Chagas. Belém, Pará. Brasil.Laboratório Central de Saúde Pública do Estado de São Paulo (LACEN-SP). Instituto Adolfo Lutz, São Paulo, SP, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, Brasil.Departamento de Imunização e Doenças Transmissíveis (DEIDT)/Secretaria de Vigilância em Saúde (SVS)/Ministério da Saúde (MS), Brasília, Distrito Federal, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, Brasil.The influenza A virus (IAV) is of a major public health concern as it causes annual epidemics and has the potential to cause pandemics. At present, the neuraminidase inhibitors (NAIs) are the most widely used anti-influenza drugs, but, more recently, the drug baloxavir marboxil (BXM), a polymerase inhibitor, has also been licensed in some countries. Mutations in the viral genes that encode the antiviral targets can lead to treatment resistance. Worldwide, a low prevalence of antiviral resistant strains has been reported. Despite that, this situation can change rapidly, and resistant strain surveillance is a priority. Thus, the aim of this was to evaluate Brazilian IAVs antiviral resistance from 2017 to 2019 through the identification of viral mutations associated with reduced inhibition of the drugs and by testing the susceptibility of IAV isolates to oseltamivir (OST), the most widely used NAI drug in the country. Initially, we analyzed 282 influenza A(H1N1)pdm09 and 455 A(H3N2) genetic sequences available on GISAID. The amino acid substitution (AAS) NA:S247N was detected in one A(H1N1)pdm09 strain.We also identifiedNA:I222V (n=6) andNA:N329K (n = 1) in A(H3N2) strains. In addition, we performed a molecular screening for NA:H275Y in 437 A(H1N1)pdm09 samples, by pyrosequencing, which revealed a single virus harboring this mutation. Furthermore, the determination of OST IC50 values for 222 A(H1N1)pdm09 and 83 A(H3N2) isolates revealed that all isolates presented a normal susceptibility profile to the drug. Interestingly, we detected one A(H3N2) virus presenting with PA:E119D AAS. Moreover, the majority of the IAV sequences had the M2:S31N adamantanes resistantmarker. In conclusion, we show a low prevalence of Brazilian IAV strains with NAI resistance markers, in accordance with what is reported worldwide, indicating that NAIs still remain an option for the treatment of influenza infections in Brazil. However, surveillance of influenza resistance should be strengthened in the country for improving the representativeness of investigated viruses and the robustness of the analysis.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZORIGINALThiagosouza_MarildaMendonça_etal_IOC_2022.pdfThiagosouza_MarildaMendonça_etal_IOC_2022.pdfapplication/pdf342099https://www.arca.fiocruz.br/bitstream/icict/56816/2/Thiagosouza_MarildaMendon%c3%a7a_etal_IOC_2022.pdfed5579239f75d6b66ae7a29bf044fdf3MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/56816/1/license.txt5a560609d32a3863062d77ff32785d58MD51icict/568162023-09-04 11:17:41.715oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352023-09-04T14:17:41Repositório Institucional da FIOCRUZ (ARCA) - 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dc.title.en_US.fl_str_mv Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons
title Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons
spellingShingle Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons
Sousa, Thiago das Chagas
Vírus da gripe A
Inibidores da neuraminidase (NA)
Oseltamivir
Baloxavir marboxiL
Adamantano
Resistência
Influenza A virus
Neuraminidase (NA) inhibitors
Oseltamivir
Baloxavir marboxiL
Adamantane
Resistance
title_short Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons
title_full Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons
title_fullStr Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons
title_full_unstemmed Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons
title_sort Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons
author Sousa, Thiago das Chagas
author_facet Sousa, Thiago das Chagas
Martins, Jessica Santa Cruz Carvalho
Miranda, Milene Dias
Garcia, Cristiana Couto
Resende, Paola Cristina
Santos, Cliomar A.
Debur, Maria do Carmo
Rodrigues, Rodrigo Ribeiro
Cavalcanti, Andrea Cony
Gregianini, Tatiana Schäffer
Iani, Felipe Campos de Melo
Pereira, Felicidade Mota
Fernandes, Sandra Bianchini
Ferreira, Jessylene de Almeida
Santos, Katia Correa de Oliveira
Motta, Fernando
Brown, David
Almeida, Walquiria Aparecida Ferreira de
Siqueira, Marilda Mendonça
Matos, Aline da Rocha
author_role author
author2 Martins, Jessica Santa Cruz Carvalho
Miranda, Milene Dias
Garcia, Cristiana Couto
Resende, Paola Cristina
Santos, Cliomar A.
Debur, Maria do Carmo
Rodrigues, Rodrigo Ribeiro
Cavalcanti, Andrea Cony
Gregianini, Tatiana Schäffer
Iani, Felipe Campos de Melo
Pereira, Felicidade Mota
Fernandes, Sandra Bianchini
Ferreira, Jessylene de Almeida
Santos, Katia Correa de Oliveira
Motta, Fernando
Brown, David
Almeida, Walquiria Aparecida Ferreira de
Siqueira, Marilda Mendonça
Matos, Aline da Rocha
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Sousa, Thiago das Chagas
Martins, Jessica Santa Cruz Carvalho
Miranda, Milene Dias
Garcia, Cristiana Couto
Resende, Paola Cristina
Santos, Cliomar A.
Debur, Maria do Carmo
Rodrigues, Rodrigo Ribeiro
Cavalcanti, Andrea Cony
Gregianini, Tatiana Schäffer
Iani, Felipe Campos de Melo
Pereira, Felicidade Mota
Fernandes, Sandra Bianchini
Ferreira, Jessylene de Almeida
Santos, Katia Correa de Oliveira
Motta, Fernando
Brown, David
Almeida, Walquiria Aparecida Ferreira de
Siqueira, Marilda Mendonça
Matos, Aline da Rocha
dc.subject.other.en_US.fl_str_mv Vírus da gripe A
Inibidores da neuraminidase (NA)
Oseltamivir
Baloxavir marboxiL
Adamantano
Resistência
topic Vírus da gripe A
Inibidores da neuraminidase (NA)
Oseltamivir
Baloxavir marboxiL
Adamantano
Resistência
Influenza A virus
Neuraminidase (NA) inhibitors
Oseltamivir
Baloxavir marboxiL
Adamantane
Resistance
dc.subject.en.en_US.fl_str_mv Influenza A virus
Neuraminidase (NA) inhibitors
Oseltamivir
Baloxavir marboxiL
Adamantane
Resistance
description Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, Brasil.
publishDate 2022
dc.date.issued.fl_str_mv 2022
dc.date.accessioned.fl_str_mv 2023-02-01T15:28:43Z
dc.date.available.fl_str_mv 2023-02-01T15:28:43Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
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status_str publishedVersion
dc.identifier.citation.fl_str_mv SOUSA, Thiago das Chagas et al. Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons. Frontiers in Public Health, 10, 944277, p. 1 - 9, Sept. 2022.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/56816
dc.identifier.issn.en_US.fl_str_mv 2296-2565
dc.identifier.doi.none.fl_str_mv 10.3389/fpubh.2022.944277
identifier_str_mv SOUSA, Thiago das Chagas et al. Low prevalence of influenza A strains with resistance markers in Brazil during 2017–2019 seasons. Frontiers in Public Health, 10, 944277, p. 1 - 9, Sept. 2022.
2296-2565
10.3389/fpubh.2022.944277
url https://www.arca.fiocruz.br/handle/icict/56816
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
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
instname_str 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 https://www.arca.fiocruz.br/bitstream/icict/56816/2/Thiagosouza_MarildaMendon%c3%a7a_etal_IOC_2022.pdf
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