Functional inhibition of host histone deacetylases (HDACs) enhances in vitro and in vivo anti-mycobacterial activity in human macrophages and in zebrafish
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | https://doi.org/10.3389/fimmu.2020.00036 http://hdl.handle.net/1843/51596 |
Resumo: | The rapid and persistent increase of drug-resistant Mycobacterium tuberculosis (Mtb) infections poses increasing global problems in combatting tuberculosis (TB), prompting for the development of alternative strategies including host-directed therapy (HDT). Since Mtb is an intracellular pathogen with a remarkable ability to manipulate host intracellular signaling pathways to escape from host defense, pharmacological reprogramming of the immune system represents a novel, potentially powerful therapeutic strategy that should be effective also against drug-resistant Mtb. Here, we found that host-pathogen interactions in Mtb-infected primary human macrophages affected host epigenetic features by modifying histone deacetylase (HDAC) transcriptomic levels. In addition, broad spectrum inhibition of HDACs enhanced the antimicrobial response of both pro-inflammatory macrophages (Mφ1) and anti-inflammatory macrophages (Mφ2), while selective inhibition of class IIa HDACs mainly decreased bacterial outgrowth in Mφ2. Moreover, chemical inhibition of HDAC activity during differentiation polarized macrophages into a more bactericidal phenotype with a concomitant decrease in the secretion levels of inflammatory cytokines. Importantly, in vivo chemical inhibition of HDAC activity in Mycobacterium marinum-infected zebrafish embryos, a well-characterized animal model for tuberculosis, significantly reduced mycobacterial burden, validating our in vitro findings in primary human macrophages. Collectively, these data identify HDACs as druggable host targets for HDT against intracellular Mtb. |
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2023-04-04T21:37:01Z2023-04-04T21:37:01Z2020-0211116https://doi.org/10.3389/fimmu.2020.000361664-3224http://hdl.handle.net/1843/51596The rapid and persistent increase of drug-resistant Mycobacterium tuberculosis (Mtb) infections poses increasing global problems in combatting tuberculosis (TB), prompting for the development of alternative strategies including host-directed therapy (HDT). Since Mtb is an intracellular pathogen with a remarkable ability to manipulate host intracellular signaling pathways to escape from host defense, pharmacological reprogramming of the immune system represents a novel, potentially powerful therapeutic strategy that should be effective also against drug-resistant Mtb. Here, we found that host-pathogen interactions in Mtb-infected primary human macrophages affected host epigenetic features by modifying histone deacetylase (HDAC) transcriptomic levels. In addition, broad spectrum inhibition of HDACs enhanced the antimicrobial response of both pro-inflammatory macrophages (Mφ1) and anti-inflammatory macrophages (Mφ2), while selective inhibition of class IIa HDACs mainly decreased bacterial outgrowth in Mφ2. Moreover, chemical inhibition of HDAC activity during differentiation polarized macrophages into a more bactericidal phenotype with a concomitant decrease in the secretion levels of inflammatory cytokines. Importantly, in vivo chemical inhibition of HDAC activity in Mycobacterium marinum-infected zebrafish embryos, a well-characterized animal model for tuberculosis, significantly reduced mycobacterial burden, validating our in vitro findings in primary human macrophages. Collectively, these data identify HDACs as druggable host targets for HDT against intracellular Mtb.O aumento rápido e persistente de infecções por Mycobacterium tuberculosis (Mtb) resistentes a medicamentos apresenta problemas globais crescentes no combate à tuberculose (TB), levando ao desenvolvimento de estratégias alternativas, incluindo terapia dirigida ao hospedeiro (HDT). Uma vez que o Mtb é um patógeno intracelular com uma notável capacidade de manipular as vias de sinalização intracelular do hospedeiro para escapar da defesa do hospedeiro, a reprogramação farmacológica do sistema imunológico representa uma nova estratégia terapêutica potencialmente poderosa que deve ser eficaz também contra o Mtb resistente a medicamentos. Aqui, descobrimos que as interações hospedeiro-patógeno em macrófagos humanos primários infectados com Mtb afetaram as características epigenéticas do hospedeiro, modificando os níveis transcriptômicos da histona desacetilase (HDAC). Além disso, a inibição de amplo espectro de HDACs aumentou a resposta antimicrobiana de macrófagos pró-inflamatórios (Mϕ1) e macrófagos anti-inflamatórios (Mϕ2), enquanto a inibição seletiva de HDACs classe IIa diminuiu principalmente o crescimento bacteriano em Mϕ2. Além disso, a inibição química da atividade de HDAC durante a diferenciação polarizou os macrófagos em um fenótipo mais bactericida com uma diminuição concomitante nos níveis de secreção de citocinas inflamatórias. É importante ressaltar que a inibição química in vivo da atividade de HDAC em embriões de peixe-zebra infectados com Mycobacterium marinum, um modelo animal bem caracterizado para tuberculose, reduziu significativamente a carga micobacteriana, validando nossos achados in vitro em macrófagos humanos primários. Coletivamente, esses dados identificam HDACs como alvos hospedeiros drogáveis para HDT contra Mtb intracelular.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorengUniversidade Federal de Minas GeraisUFMGBrasilFAR - DEPARTAMENTO DE ANÁLISES CLÍNICAS E TOXICOLÓGICASFrontiers in ImmunologyTuberculoseRegulação epigenéticaHistona desacetilasesMacrófagosTuberculosisHost-directed therapyEpigenetic regulationHistone deacetylases (HDAC)Human macrophagesFunctional inhibition of host histone deacetylases (HDACs) enhances in vitro and in vivo anti-mycobacterial activity in human macrophages and in zebrafishinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttps://www.frontiersin.org/articles/10.3389/fimmu.2020.00036/fullJôsimar Dornelas MoreiraBjørn E. V. KochSuzanne van VeenKimberley V. WalburgFrank VrielingTânia Mara Pinto Dabés GuimarãesAnnemarie H. MeijerHerman P. SpainkTom H. M. OttenhoffMariëlle C. HaksMatthias T. Heemskerapplication/pdfinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGORIGINALFunctional inhibition of host histone deacetylases (HDACS) enhances in vitro and in vivo anti-mycobacterial activity in human macrophages and in zebrafish.pdfFunctional inhibition of host histone deacetylases (HDACS) enhances in vitro and in vivo anti-mycobacterial activity in human macrophages and in zebrafish.pdfapplication/pdf1445476https://repositorio.ufmg.br/bitstream/1843/51596/2/Functional%20inhibition%20of%20host%20histone%20deacetylases%20%28HDACS%29%20enhances%20in%20vitro%20and%20in%20vivo%20anti-mycobacterial%20activity%20in%20human%20macrophages%20and%20in%20zebrafish.pdf6eb39d4011d20b3d407b173c65b30433MD52LICENSELicense.txtLicense.txttext/plain; charset=utf-82042https://repositorio.ufmg.br/bitstream/1843/51596/1/License.txtfa505098d172de0bc8864fc1287ffe22MD511843/515962023-04-04 20:36:22.419oai:repositorio.ufmg.br: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Repositório de PublicaçõesPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-04-04T23:36:22Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
dc.title.pt_BR.fl_str_mv |
Functional inhibition of host histone deacetylases (HDACs) enhances in vitro and in vivo anti-mycobacterial activity in human macrophages and in zebrafish |
title |
Functional inhibition of host histone deacetylases (HDACs) enhances in vitro and in vivo anti-mycobacterial activity in human macrophages and in zebrafish |
spellingShingle |
Functional inhibition of host histone deacetylases (HDACs) enhances in vitro and in vivo anti-mycobacterial activity in human macrophages and in zebrafish Jôsimar Dornelas Moreira Tuberculosis Host-directed therapy Epigenetic regulation Histone deacetylases (HDAC) Human macrophages Tuberculose Regulação epigenética Histona desacetilases Macrófagos |
title_short |
Functional inhibition of host histone deacetylases (HDACs) enhances in vitro and in vivo anti-mycobacterial activity in human macrophages and in zebrafish |
title_full |
Functional inhibition of host histone deacetylases (HDACs) enhances in vitro and in vivo anti-mycobacterial activity in human macrophages and in zebrafish |
title_fullStr |
Functional inhibition of host histone deacetylases (HDACs) enhances in vitro and in vivo anti-mycobacterial activity in human macrophages and in zebrafish |
title_full_unstemmed |
Functional inhibition of host histone deacetylases (HDACs) enhances in vitro and in vivo anti-mycobacterial activity in human macrophages and in zebrafish |
title_sort |
Functional inhibition of host histone deacetylases (HDACs) enhances in vitro and in vivo anti-mycobacterial activity in human macrophages and in zebrafish |
author |
Jôsimar Dornelas Moreira |
author_facet |
Jôsimar Dornelas Moreira Bjørn E. V. Koch Suzanne van Veen Kimberley V. Walburg Frank Vrieling Tânia Mara Pinto Dabés Guimarães Annemarie H. Meijer Herman P. Spaink Tom H. M. Ottenhoff Mariëlle C. Haks Matthias T. Heemsker |
author_role |
author |
author2 |
Bjørn E. V. Koch Suzanne van Veen Kimberley V. Walburg Frank Vrieling Tânia Mara Pinto Dabés Guimarães Annemarie H. Meijer Herman P. Spaink Tom H. M. Ottenhoff Mariëlle C. Haks Matthias T. Heemsker |
author2_role |
author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Jôsimar Dornelas Moreira Bjørn E. V. Koch Suzanne van Veen Kimberley V. Walburg Frank Vrieling Tânia Mara Pinto Dabés Guimarães Annemarie H. Meijer Herman P. Spaink Tom H. M. Ottenhoff Mariëlle C. Haks Matthias T. Heemsker |
dc.subject.por.fl_str_mv |
Tuberculosis Host-directed therapy Epigenetic regulation Histone deacetylases (HDAC) Human macrophages |
topic |
Tuberculosis Host-directed therapy Epigenetic regulation Histone deacetylases (HDAC) Human macrophages Tuberculose Regulação epigenética Histona desacetilases Macrófagos |
dc.subject.other.pt_BR.fl_str_mv |
Tuberculose Regulação epigenética Histona desacetilases Macrófagos |
description |
The rapid and persistent increase of drug-resistant Mycobacterium tuberculosis (Mtb) infections poses increasing global problems in combatting tuberculosis (TB), prompting for the development of alternative strategies including host-directed therapy (HDT). Since Mtb is an intracellular pathogen with a remarkable ability to manipulate host intracellular signaling pathways to escape from host defense, pharmacological reprogramming of the immune system represents a novel, potentially powerful therapeutic strategy that should be effective also against drug-resistant Mtb. Here, we found that host-pathogen interactions in Mtb-infected primary human macrophages affected host epigenetic features by modifying histone deacetylase (HDAC) transcriptomic levels. In addition, broad spectrum inhibition of HDACs enhanced the antimicrobial response of both pro-inflammatory macrophages (Mφ1) and anti-inflammatory macrophages (Mφ2), while selective inhibition of class IIa HDACs mainly decreased bacterial outgrowth in Mφ2. Moreover, chemical inhibition of HDAC activity during differentiation polarized macrophages into a more bactericidal phenotype with a concomitant decrease in the secretion levels of inflammatory cytokines. Importantly, in vivo chemical inhibition of HDAC activity in Mycobacterium marinum-infected zebrafish embryos, a well-characterized animal model for tuberculosis, significantly reduced mycobacterial burden, validating our in vitro findings in primary human macrophages. Collectively, these data identify HDACs as druggable host targets for HDT against intracellular Mtb. |
publishDate |
2020 |
dc.date.issued.fl_str_mv |
2020-02 |
dc.date.accessioned.fl_str_mv |
2023-04-04T21:37:01Z |
dc.date.available.fl_str_mv |
2023-04-04T21:37:01Z |
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.uri.fl_str_mv |
http://hdl.handle.net/1843/51596 |
dc.identifier.doi.pt_BR.fl_str_mv |
https://doi.org/10.3389/fimmu.2020.00036 |
dc.identifier.issn.pt_BR.fl_str_mv |
1664-3224 |
url |
https://doi.org/10.3389/fimmu.2020.00036 http://hdl.handle.net/1843/51596 |
identifier_str_mv |
1664-3224 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.none.fl_str_mv |
Frontiers in Immunology |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais |
dc.publisher.initials.fl_str_mv |
UFMG |
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Brasil |
dc.publisher.department.fl_str_mv |
FAR - DEPARTAMENTO DE ANÁLISES CLÍNICAS E TOXICOLÓGICAS |
publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais |
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reponame:Repositório Institucional da UFMG instname:Universidade Federal de Minas Gerais (UFMG) instacron:UFMG |
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