Resistance against Leishmania major infection depends on microbiota-guided macrophage activation
Autor(a) principal: | |
---|---|
Data de Publicação: | 2021 |
Outros Autores: | , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | https://doi.org/10.3389/fimmu.2021.730437 http://hdl.handle.net/1843/56243 https://orcid.org/0000-0001-8730-7336 https://orcid.org/0000-0002-4466-8868 https://orcid.org/0000-0001-5481-9618 |
Resumo: | Innate immune cells present a dual role during leishmaniasis: they constitute the first line of host defense but are also the main host cells for the parasite. Response against the infection that results in the control of parasite growth and lesion healing depends on activation of macrophages into a classical activated phenotype. We report an essential role for the microbiota in driving macrophage and monocyte-derived macrophage activation towards a resistance phenotype against Leishmania major infection in mice. Both germ-free and dysbiotic mice showed a higher number of myeloid innate cells in lesions and increased number of infected cells, mainly dermal resident and inflammatory macrophages. Despite developing a Th1 immune response characterized by the same levels of IFN-γ production as the conventional mice, germ-free mice presented reduced numbers of iNOS+ macrophages at the peak of infection. Absence or disturbance of host microbiota impaired the capacity of bone marrow-derived macrophage to be activated for Leishmania killing in vitro, even when stimulated by Th1 cytokines. These cells presented reduced expression of inos mRNA, and diminished production of microbicidal molecules, such as ROS, while presenting a permissive activation status, characterized by increased expression of arginase I and il-10 mRNA and higher arginase activity. Colonization of germ-free mice with complete microbiota from conventional mice rescued their ability to control the infection. This study demonstrates the essential role of host microbiota on innate immune response against L. major infection, driving host macrophages to a resistance phenotype. |
id |
UFMG_5d9d70468359737f4055d78d66df9a5c |
---|---|
oai_identifier_str |
oai:repositorio.ufmg.br:1843/56243 |
network_acronym_str |
UFMG |
network_name_str |
Repositório Institucional da UFMG |
repository_id_str |
|
spelling |
2023-07-14T19:14:12Z2023-07-14T19:14:12Z202112https://doi.org/10.3389/fimmu.2021.7304371664-3224http://hdl.handle.net/1843/56243https://orcid.org/0000-0001-8730-7336https://orcid.org/0000-0002-4466-8868https://orcid.org/0000-0001-5481-9618Innate immune cells present a dual role during leishmaniasis: they constitute the first line of host defense but are also the main host cells for the parasite. Response against the infection that results in the control of parasite growth and lesion healing depends on activation of macrophages into a classical activated phenotype. We report an essential role for the microbiota in driving macrophage and monocyte-derived macrophage activation towards a resistance phenotype against Leishmania major infection in mice. Both germ-free and dysbiotic mice showed a higher number of myeloid innate cells in lesions and increased number of infected cells, mainly dermal resident and inflammatory macrophages. Despite developing a Th1 immune response characterized by the same levels of IFN-γ production as the conventional mice, germ-free mice presented reduced numbers of iNOS+ macrophages at the peak of infection. Absence or disturbance of host microbiota impaired the capacity of bone marrow-derived macrophage to be activated for Leishmania killing in vitro, even when stimulated by Th1 cytokines. These cells presented reduced expression of inos mRNA, and diminished production of microbicidal molecules, such as ROS, while presenting a permissive activation status, characterized by increased expression of arginase I and il-10 mRNA and higher arginase activity. Colonization of germ-free mice with complete microbiota from conventional mice rescued their ability to control the infection. This study demonstrates the essential role of host microbiota on innate immune response against L. major infection, driving host macrophages to a resistance phenotype.As células imunes inatas apresentam um duplo papel durante a leishmaniose: elas constituem a primeira linha de defesa do hospedeiro, mas também são as principais células do hospedeiro para o parasita. A resposta contra a infecção que resulta no controle do crescimento do parasita e cicatrização da lesão depende da ativação de macrófagos em um fenótipo ativado clássico. Relatamos um papel essencial para a microbiota na condução da ativação de macrófagos e macrófagos derivados de monócitos em direção a um fenótipo de resistência contra a infecção por Leishmania major em camundongos. Camundongos germ-free e disbióticos apresentaram maior número de células inatas mieloides nas lesões e maior número de células infectadas, principalmente residentes dérmicas e macrófagos inflamatórios. Apesar de desenvolver uma resposta imune Th1 caracterizada pelos mesmos níveis de produção de IFN-γ que os camundongos convencionais, os camundongos germ-free apresentaram número reduzido de macrófagos iNOS+ no pico da infecção. A ausência ou distúrbio da microbiota do hospedeiro prejudicou a capacidade do macrófago derivado da medula óssea de ser ativado para matar Leishmania in vitro, mesmo quando estimulado por citocinas Th1. Essas células apresentaram expressão reduzida de mRNA de inos e produção diminuída de moléculas microbicidas, como ROS, enquanto apresentavam um estado de ativação permissiva, caracterizado por expressão aumentada de mRNA de arginase I e il-10 e maior atividade de arginase. A colonização de camundongos germ-free com microbiota completa de camundongos convencionais resgatou sua capacidade de controlar a infecção. Este estudo demonstra o papel essencial da microbiota do hospedeiro na resposta imune inata contra a infecção por L. major, conduzindo os macrófagos do hospedeiro a um fenótipo de resistência.CNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas GeraisCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorengUniversidade Federal de Minas GeraisUFMGBrasilICB - DEPARTAMENTO DE BIOQUÍMICA E IMUNOLOGIAFrontiers in ImmunologyLeishmania majorMacrófagosMonócitosÓxido NítricoMicrobiotaLeishmania majorMacrophagemonocytecell-activationnitric oxidemicrobiotaResistance against Leishmania major infection depends on microbiota-guided macrophage activationA resistência contra a infecção por Leishmania major depende da ativação de macrófagos guiada pela microbiotainfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttps://www.frontiersin.org/articles/10.3389/fimmu.2021.730437/fullMateus Eustáquio de Moura LopesLiliane Martins dos SantosDavid SacksLeda Quercia VieiraMatheus B. H. Carneiroapplication/pdfinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMGLICENSELicense.txtLicense.txttext/plain; charset=utf-82042https://repositorio.ufmg.br/bitstream/1843/56243/1/License.txtfa505098d172de0bc8864fc1287ffe22MD51ORIGINALResistance against leishmania major infection depends on microbiota-guided macrophage activation.pdfResistance against leishmania major infection depends on microbiota-guided macrophage activation.pdfapplication/pdf2253553https://repositorio.ufmg.br/bitstream/1843/56243/2/Resistance%20against%20leishmania%20major%20infection%20depends%20on%20microbiota-guided%20macrophage%20activation.pdf7b736187d2dfcf8df62d564a960aacb9MD521843/562432023-07-14 16:14:12.542oai:repositorio.ufmg.br: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Repositório de PublicaçõesPUBhttps://repositorio.ufmg.br/oaiopendoar:2023-07-14T19:14:12Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
dc.title.pt_BR.fl_str_mv |
Resistance against Leishmania major infection depends on microbiota-guided macrophage activation |
dc.title.alternative.pt_BR.fl_str_mv |
A resistência contra a infecção por Leishmania major depende da ativação de macrófagos guiada pela microbiota |
title |
Resistance against Leishmania major infection depends on microbiota-guided macrophage activation |
spellingShingle |
Resistance against Leishmania major infection depends on microbiota-guided macrophage activation Mateus Eustáquio de Moura Lopes Leishmania major Macrophage monocyte cell-activation nitric oxide microbiota Leishmania major Macrófagos Monócitos Óxido Nítrico Microbiota |
title_short |
Resistance against Leishmania major infection depends on microbiota-guided macrophage activation |
title_full |
Resistance against Leishmania major infection depends on microbiota-guided macrophage activation |
title_fullStr |
Resistance against Leishmania major infection depends on microbiota-guided macrophage activation |
title_full_unstemmed |
Resistance against Leishmania major infection depends on microbiota-guided macrophage activation |
title_sort |
Resistance against Leishmania major infection depends on microbiota-guided macrophage activation |
author |
Mateus Eustáquio de Moura Lopes |
author_facet |
Mateus Eustáquio de Moura Lopes Liliane Martins dos Santos David Sacks Leda Quercia Vieira Matheus B. H. Carneiro |
author_role |
author |
author2 |
Liliane Martins dos Santos David Sacks Leda Quercia Vieira Matheus B. H. Carneiro |
author2_role |
author author author author |
dc.contributor.author.fl_str_mv |
Mateus Eustáquio de Moura Lopes Liliane Martins dos Santos David Sacks Leda Quercia Vieira Matheus B. H. Carneiro |
dc.subject.por.fl_str_mv |
Leishmania major Macrophage monocyte cell-activation nitric oxide microbiota |
topic |
Leishmania major Macrophage monocyte cell-activation nitric oxide microbiota Leishmania major Macrófagos Monócitos Óxido Nítrico Microbiota |
dc.subject.other.pt_BR.fl_str_mv |
Leishmania major Macrófagos Monócitos Óxido Nítrico Microbiota |
description |
Innate immune cells present a dual role during leishmaniasis: they constitute the first line of host defense but are also the main host cells for the parasite. Response against the infection that results in the control of parasite growth and lesion healing depends on activation of macrophages into a classical activated phenotype. We report an essential role for the microbiota in driving macrophage and monocyte-derived macrophage activation towards a resistance phenotype against Leishmania major infection in mice. Both germ-free and dysbiotic mice showed a higher number of myeloid innate cells in lesions and increased number of infected cells, mainly dermal resident and inflammatory macrophages. Despite developing a Th1 immune response characterized by the same levels of IFN-γ production as the conventional mice, germ-free mice presented reduced numbers of iNOS+ macrophages at the peak of infection. Absence or disturbance of host microbiota impaired the capacity of bone marrow-derived macrophage to be activated for Leishmania killing in vitro, even when stimulated by Th1 cytokines. These cells presented reduced expression of inos mRNA, and diminished production of microbicidal molecules, such as ROS, while presenting a permissive activation status, characterized by increased expression of arginase I and il-10 mRNA and higher arginase activity. Colonization of germ-free mice with complete microbiota from conventional mice rescued their ability to control the infection. This study demonstrates the essential role of host microbiota on innate immune response against L. major infection, driving host macrophages to a resistance phenotype. |
publishDate |
2021 |
dc.date.issued.fl_str_mv |
2021 |
dc.date.accessioned.fl_str_mv |
2023-07-14T19:14:12Z |
dc.date.available.fl_str_mv |
2023-07-14T19:14:12Z |
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/1843/56243 |
dc.identifier.doi.pt_BR.fl_str_mv |
https://doi.org/10.3389/fimmu.2021.730437 |
dc.identifier.issn.pt_BR.fl_str_mv |
1664-3224 |
dc.identifier.orcid.pt_BR.fl_str_mv |
https://orcid.org/0000-0001-8730-7336 https://orcid.org/0000-0002-4466-8868 https://orcid.org/0000-0001-5481-9618 |
url |
https://doi.org/10.3389/fimmu.2021.730437 http://hdl.handle.net/1843/56243 https://orcid.org/0000-0001-8730-7336 https://orcid.org/0000-0002-4466-8868 https://orcid.org/0000-0001-5481-9618 |
identifier_str_mv |
1664-3224 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.pt_BR.fl_str_mv |
Frontiers in Immunology |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais |
dc.publisher.initials.fl_str_mv |
UFMG |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
ICB - DEPARTAMENTO DE BIOQUÍMICA E IMUNOLOGIA |
publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFMG instname:Universidade Federal de Minas Gerais (UFMG) instacron:UFMG |
instname_str |
Universidade Federal de Minas Gerais (UFMG) |
instacron_str |
UFMG |
institution |
UFMG |
reponame_str |
Repositório Institucional da UFMG |
collection |
Repositório Institucional da UFMG |
bitstream.url.fl_str_mv |
https://repositorio.ufmg.br/bitstream/1843/56243/1/License.txt https://repositorio.ufmg.br/bitstream/1843/56243/2/Resistance%20against%20leishmania%20major%20infection%20depends%20on%20microbiota-guided%20macrophage%20activation.pdf |
bitstream.checksum.fl_str_mv |
fa505098d172de0bc8864fc1287ffe22 7b736187d2dfcf8df62d564a960aacb9 |
bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 |
repository.name.fl_str_mv |
Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG) |
repository.mail.fl_str_mv |
|
_version_ |
1797971199236505600 |