HIF-1α relevance in necrosis of mycobacterium avium-induced granulomas

Detalhes bibliográficos
Autor(a) principal: Cardoso, Marcos Levi dos Santos
Data de Publicação: 2014
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10773/13858
Resumo: The establishment of mycobacterial infection is characterized by the formation of granulomas, which are well-organized aggregates of immune cells, namely infected macrophages. The granuloma main function is to constrain and prevent dissemination of the mycobacteria, while concentrating the immune response to a limited area. In some cases these lesions can grow progressively into large granulomas which can undergo central necrosis leading to their caseation. However, the mechanism underlying this type of pathology is still poorly understood. It has been reported that reduced vascularization of granulomas may be one essential mechanism for caseation and some studies have demonstrated severely hypoxic regions at the center of the granuloma. Under hypoxic conditions the immune cells need to adapt to low oxygen conditions in order to remain functionally active. Thus, the hypoxia-inducible factor – 1 alpha (HIF-1α) has emerged as a master regulator of the hypoxia adaptation system, mediating a wide range of physiological and cellular mechanisms. The Appelberg group has developed a granuloma necrosis model that mimics the human pathology of Mycobacterium tuberculosis, using C57BL/6 mice intravenously infected with a low dose of a highly virulent strain of Mycobacterium avium (ATCC 25291). Such mice develop granulomas that, at 4 months of infection, exhibit central necrosis. To determine the relevance of HIF-1α during M. avium infection we used a mouse strain deleted of HIF-1α under the Cre-lox system in the myeloid cell lineage. The results obtained indicate that HIF-1α deficient mice are more susceptible to the infection and that the onset of necrotic granulomas is faster.
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spelling HIF-1α relevance in necrosis of mycobacterium avium-induced granulomasBiologia moleculaBactérias patogénicasInfecções por bactériasGranulomaNecroseHipoxiaSistema imunitárioMycobacterium aviumThe establishment of mycobacterial infection is characterized by the formation of granulomas, which are well-organized aggregates of immune cells, namely infected macrophages. The granuloma main function is to constrain and prevent dissemination of the mycobacteria, while concentrating the immune response to a limited area. In some cases these lesions can grow progressively into large granulomas which can undergo central necrosis leading to their caseation. However, the mechanism underlying this type of pathology is still poorly understood. It has been reported that reduced vascularization of granulomas may be one essential mechanism for caseation and some studies have demonstrated severely hypoxic regions at the center of the granuloma. Under hypoxic conditions the immune cells need to adapt to low oxygen conditions in order to remain functionally active. Thus, the hypoxia-inducible factor – 1 alpha (HIF-1α) has emerged as a master regulator of the hypoxia adaptation system, mediating a wide range of physiological and cellular mechanisms. The Appelberg group has developed a granuloma necrosis model that mimics the human pathology of Mycobacterium tuberculosis, using C57BL/6 mice intravenously infected with a low dose of a highly virulent strain of Mycobacterium avium (ATCC 25291). Such mice develop granulomas that, at 4 months of infection, exhibit central necrosis. To determine the relevance of HIF-1α during M. avium infection we used a mouse strain deleted of HIF-1α under the Cre-lox system in the myeloid cell lineage. The results obtained indicate that HIF-1α deficient mice are more susceptible to the infection and that the onset of necrotic granulomas is faster.O desenvolvimento da infeção por micobactérias é caracterizado pela formação de granulomas, os quais são agregados bem organizados de células do sistema imunitário, nomeadamente macrófagos infetados. A principal função do granuloma é restringir e prevenir a disseminação da micobactéria permitindo que a resposta imunitária seja centrada numa área limitada. Por vezes, estas lesões aumentam em tamanho, progredindo para um processo de necrose central levando à caseação tecidular. Contudo, o mecanismo subjacente a este tipo de patologia é pouco compreendido. Tem sido descrito que a redução da vascularização dos granulomas é essencial para a sua caseação e alguns estudos demonstraram que o centro do granuloma é altamente hipóxico. Em condições de hipóxia as células do sistema imunitário necessitam de se adaptar rapidamente a concentrações de oxigénio baixas de forma a permanecerem funcionalmente ativas. Assim, o fator indutível por hipóxia – 1 alfa (HIF-1α) tem emergido como o principal regulador do sistema de adaptação à hipoxia, mediando uma série de mecanismos fisiológicos e celulares. O grupo de investigação da responsabilidade do Professor Appelberg, desenvolveu um modelo de estudo que mimetiza a necrose do granuloma observado durante a infeção por Mycobacterium tuberculosis em humanos. Este modelo consiste na infeção intravenosa de murganhos C57BL/6 com uma dose baixa de uma estirpe altamente virulenta de Mycobacterium avium (ATCC 25291). Estes murganhos desenvolvem granulomas necrosados após 4 meses de infeção. Para determinar a relevância do HIF-1α durante a infeção por M. avium, foram utilizados murganhos com células da linhagem mielóide deletadas para o fator HIF-1α sobre o controlo do sistema Cre-lox. Os resultados obtidos indicam que os murganhos deficientes em HIF-1α são mais suscetíveis à infeção e em que o aparecimento de granulomas necróticos é antecipado.Universidade de Aveiro2015-04-20T17:49:38Z2014-01-01T00:00:00Z2014info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10773/13858engCardoso, Marcos Levi dos Santosinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-02-22T11:25:16Zoai:ria.ua.pt:10773/13858Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T02:49:36.035554Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv HIF-1α relevance in necrosis of mycobacterium avium-induced granulomas
title HIF-1α relevance in necrosis of mycobacterium avium-induced granulomas
spellingShingle HIF-1α relevance in necrosis of mycobacterium avium-induced granulomas
Cardoso, Marcos Levi dos Santos
Biologia molecula
Bactérias patogénicas
Infecções por bactérias
Granuloma
Necrose
Hipoxia
Sistema imunitário
Mycobacterium avium
title_short HIF-1α relevance in necrosis of mycobacterium avium-induced granulomas
title_full HIF-1α relevance in necrosis of mycobacterium avium-induced granulomas
title_fullStr HIF-1α relevance in necrosis of mycobacterium avium-induced granulomas
title_full_unstemmed HIF-1α relevance in necrosis of mycobacterium avium-induced granulomas
title_sort HIF-1α relevance in necrosis of mycobacterium avium-induced granulomas
author Cardoso, Marcos Levi dos Santos
author_facet Cardoso, Marcos Levi dos Santos
author_role author
dc.contributor.author.fl_str_mv Cardoso, Marcos Levi dos Santos
dc.subject.por.fl_str_mv Biologia molecula
Bactérias patogénicas
Infecções por bactérias
Granuloma
Necrose
Hipoxia
Sistema imunitário
Mycobacterium avium
topic Biologia molecula
Bactérias patogénicas
Infecções por bactérias
Granuloma
Necrose
Hipoxia
Sistema imunitário
Mycobacterium avium
description The establishment of mycobacterial infection is characterized by the formation of granulomas, which are well-organized aggregates of immune cells, namely infected macrophages. The granuloma main function is to constrain and prevent dissemination of the mycobacteria, while concentrating the immune response to a limited area. In some cases these lesions can grow progressively into large granulomas which can undergo central necrosis leading to their caseation. However, the mechanism underlying this type of pathology is still poorly understood. It has been reported that reduced vascularization of granulomas may be one essential mechanism for caseation and some studies have demonstrated severely hypoxic regions at the center of the granuloma. Under hypoxic conditions the immune cells need to adapt to low oxygen conditions in order to remain functionally active. Thus, the hypoxia-inducible factor – 1 alpha (HIF-1α) has emerged as a master regulator of the hypoxia adaptation system, mediating a wide range of physiological and cellular mechanisms. The Appelberg group has developed a granuloma necrosis model that mimics the human pathology of Mycobacterium tuberculosis, using C57BL/6 mice intravenously infected with a low dose of a highly virulent strain of Mycobacterium avium (ATCC 25291). Such mice develop granulomas that, at 4 months of infection, exhibit central necrosis. To determine the relevance of HIF-1α during M. avium infection we used a mouse strain deleted of HIF-1α under the Cre-lox system in the myeloid cell lineage. The results obtained indicate that HIF-1α deficient mice are more susceptible to the infection and that the onset of necrotic granulomas is faster.
publishDate 2014
dc.date.none.fl_str_mv 2014-01-01T00:00:00Z
2014
2015-04-20T17:49:38Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10773/13858
url http://hdl.handle.net/10773/13858
dc.language.iso.fl_str_mv eng
language eng
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dc.publisher.none.fl_str_mv Universidade de Aveiro
publisher.none.fl_str_mv Universidade de Aveiro
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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