ATPasas tipo P2 como blancos para la atenuación de Mycobacterium tuberculosis.

ilustraciones, fotografías, graficas, tablas

Autores:: Maya Hoyos, Milena

Tipo de recurso:: Doctoral thesis

Fecha de publicación:: 2021

Institución:: Universidad Nacional de Colombia

Repositorio:: Universidad Nacional de Colombia

Idioma:: spa

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network_acronym_str	UNACIONAL2
network_name_str	Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv	ATPasas tipo P2 como blancos para la atenuación de Mycobacterium tuberculosis.
dc.title.translated.eng.fl_str_mv	P2-type ATPases as targets for the attenuation of Mycobacterium tuberculosis.
title	ATPasas tipo P2 como blancos para la atenuación de Mycobacterium tuberculosis.
spellingShingle	ATPasas tipo P2 como blancos para la atenuación de Mycobacterium tuberculosis. 610 - Medicina y salud::616 - Enfermedades Mycobacterium tuberculosis Mycobacterium tuberculosis ATPasas tipo P Cepas atenuadas Técnica de recombinería Calcio P-type ATPase Attenuated strains Mycobacterial recombineering
title_short	ATPasas tipo P2 como blancos para la atenuación de Mycobacterium tuberculosis.
title_full	ATPasas tipo P2 como blancos para la atenuación de Mycobacterium tuberculosis.
title_fullStr	ATPasas tipo P2 como blancos para la atenuación de Mycobacterium tuberculosis.
title_full_unstemmed	ATPasas tipo P2 como blancos para la atenuación de Mycobacterium tuberculosis.
title_sort	ATPasas tipo P2 como blancos para la atenuación de Mycobacterium tuberculosis.
dc.creator.fl_str_mv	Maya Hoyos, Milena
dc.contributor.advisor.none.fl_str_mv	Soto Ospina, Carlos Yesid
dc.contributor.author.none.fl_str_mv	Maya Hoyos, Milena
dc.contributor.researchgroup.spa.fl_str_mv	Bioquímica y Biología Molecular de las Micobacterias
dc.subject.ddc.spa.fl_str_mv	610 - Medicina y salud::616 - Enfermedades
topic	610 - Medicina y salud::616 - Enfermedades Mycobacterium tuberculosis Mycobacterium tuberculosis ATPasas tipo P Cepas atenuadas Técnica de recombinería Calcio P-type ATPase Attenuated strains Mycobacterial recombineering
dc.subject.other.spa.fl_str_mv	Mycobacterium tuberculosis
dc.subject.proposal.spa.fl_str_mv	Mycobacterium tuberculosis ATPasas tipo P Cepas atenuadas Técnica de recombinería Calcio
dc.subject.proposal.eng.fl_str_mv	P-type ATPase Attenuated strains Mycobacterial recombineering
description	ilustraciones, fotografías, graficas, tablas
publishDate	2021
dc.date.accessioned.none.fl_str_mv	2021-09-27T21:32:11Z
dc.date.available.none.fl_str_mv	2021-09-27T21:32:11Z
dc.date.issued.none.fl_str_mv	2021-04
dc.type.spa.fl_str_mv	Trabajo de grado - Doctorado
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/doctoralThesis
dc.type.version.spa.fl_str_mv	info:eu-repo/semantics/acceptedVersion
dc.type.coar.spa.fl_str_mv	http://purl.org/coar/resource_type/c_db06
dc.type.content.spa.fl_str_mv	Text
dc.type.redcol.spa.fl_str_mv	http://purl.org/redcol/resource_type/TD
format	http://purl.org/coar/resource_type/c_db06
status_str	acceptedVersion
dc.identifier.uri.none.fl_str_mv	https://repositorio.unal.edu.co/handle/unal/80314
dc.identifier.instname.spa.fl_str_mv	Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.unal.edu.co/
url	https://repositorio.unal.edu.co/handle/unal/80314 https://repositorio.unal.edu.co/
identifier_str_mv	Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv	spa
language	spa
dc.relation.indexed.spa.fl_str_mv	N/A
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dc.publisher.program.spa.fl_str_mv	Bogotá - Ciencias - Doctorado en Ciencias - Bioquímica
dc.publisher.department.spa.fl_str_mv	Departamento de Química
dc.publisher.faculty.spa.fl_str_mv	Facultad de Ciencias
dc.publisher.place.spa.fl_str_mv	Bogotá, Colombia
dc.publisher.branch.spa.fl_str_mv	Universidad Nacional de Colombia - Sede Bogotá
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spelling	Atribución-NoComercial 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Soto Ospina, Carlos Yesida5b5bbad5c61bb4a64f522a1f05590adMaya Hoyos, Milenad63e6516387cc7e8659855c2048aebe8600Bioquímica y Biología Molecular de las Micobacterias2021-09-27T21:32:11Z2021-09-27T21:32:11Z2021-04https://repositorio.unal.edu.co/handle/unal/80314Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, fotografías, graficas, tablasLa tuberculosis (TB) es una enfermedad infecciosa causada por el bacilo ácido alcohol resistente Mycobacterium tuberculosis (Mtb). La TB es una amenaza para la salud pública, debido a su alta incidencia, la aparición de cepas multi-fármaco-resistentes (MDR) y extremadamente-fármaco-resistentes (XDR), la coinfección con VIH y la eficacia limitada de la vacuna BCG. El diseño de nuevas estrategias de control requiere una mejor comprensión de los mecanismos moleculares utilizados por Mtb para ser un patógeno intracelular tan exitoso. En este sentido, algunos estudios han sugerido la importancia de las ATPasas tipo P en la fisiología y la supervivencia intracelular de las micobacterias. Un meta-análisis del perfil transcripcional de las ATPasas tipo P de Mtb bajo condiciones de estrés como hipoxia, estrés oxidativo, inanición, intoxicación por agentes químicos y procesos de infección in vitro e in vivo, evidenció la expresión diferencial de estos transportadores frente a estas condiciones. De las 12 ATPasas tipo P presentes en el genoma de Mtb, CtpF, que codifica para un transportador de Ca2+, es la ATPasa que muestra mayores niveles de transcripción en las diferentes condiciones de estrés. Particularmente, varias ATPasas tipo P (ctpF, ctpG, ctpC, ctpH y ctpV) exhibieron un aumento en los niveles de expresión durante la infección de macrófagos humanos, sugiriendo la importancia de dichas proteínas en los procesos de infección. Considerando la relevancia funcional de las ATPasas tipo P, el objetivo principal de este trabajo fue evaluar el efecto de la deleción de ATPasas tipo P transportadoras de metales alcalino/alcalinotérreos en la viabilidad y virulencia de Mtb. Para lograr este objetivo, mediante técnicas de recombinería se construyeron los mutantes defectivos en los genes ctpF y ctpH de Mtb, y a partir de distintos análisis funcionales con las cepas mutantes, se demostró que ambos transportadores están implicados en el eflujo de Ca2+. Adicionalmente, las cepas mutantes (MtbΔctpF y MtbΔctpH) mostraron hipersensibilidad frente agentes oxidantes en comparación con la cepa tipo silvestre (MtbWT), indicando un vinculo entre el transporte de Ca2+ y los mecanismos que utiliza el bacilo para neutralizar especies reactivas del ambiente intrafagosomal. Por otro lado, se evaluó en un modelo celular y animal el efecto de la deleción del gen ctpF en la virulencia Mtb. Así, se evidenció que dicha mutación genera una disminución significativa en la capacidad replicativa de Mtb en macrófagos alveolares murinos de la línea celular MH-S. Asimismo, se comparó la virulencia de las cepas MtbΔctpF y MtbWT en un ensayo de sobrevida en ratones BALB/c, encontrando que los ratones infectados con la cepa mutante mostraban mayor tiempo medio de supervivencia, sugiriendo la atenuación de la cepa mutante. Finalmente, se comprobó la existencia de estrategias complementarias que permiten contrarrestar deficiencias en el transporte iónico mediado por las ATPasa tipo P en Mtb. En efecto, se encontró que la cepa MtbΔctpF sobreexpresa el gen ctpH frente a concentraciones tóxicas de Ca2+ y durante los procesos de infección in vitro. De manera similar, el mutante MtbΔctpH sobreexpresó el gen ctpF bajo condiciones tóxicas de Ca2+, sugiriendo una posible actividad compensatoria entre CtpF y CtpH en Mtb. En general, los resultados obtenidos en este trabajo demuestran que las Ca+2-ATPasas están involucradas en la respuesta frente sustancias tóxicas, siendo fundamentales para la supervivencia celular de Mtb. Además, CtpF es relevante para la proliferación intracelular, y su deleción genera atenuación del bacilo tuberculoso en un modelo experimental de TB pulmonar. De esta manera, CtpF es fundamental para la virulencia de Mtb, por lo que podría considerarse un interesante blanco de atenuación. (texto tomado de la fuente)Tuberculosis (TB) is an infectious disease caused by the acid and alcohol-resistant bacillus Mycobacterium tuberculosis (Mtb). TB is considered a public health threat due to its high incidence, the emergence of drug-resistant strains (MDR and XDR), coinfection with HIV, and the limited efficacy of the BCG vaccine. Consequently, the design of new TB control strategies relies on a better comprehension of the molecular mechanisms used by Mtb to be a successful intracellular pathogen. In this sense, some studies have suggested that P-type ATPases are relevant to the physiology and intracellular survival of mycobacteria. Specifically, a meta-analysis of the transcriptional levels of Mtb P-type ATPases under conditions of hypoxia, oxidative stress, starvation, intoxication by chemical agents, and in vitro and in vivo infection processes indicated that these transporters are differentially expressed in these situations. Among the 12 P-type ATPases encoded in the Mtb genome, CtpF encodes a Ca2+ transporter and is the most activated against the conditions studied. Furthermore, several P-type ATPases (ctpF, ctpG, ctpC, ctpH, and ctpV) show over-expression during infection of human macrophages, suggesting the relevance of these proteins in the infection process. Therefore, the main objective of this study was to evaluate the effect of the deletion of alkali/alkaline earth metal-transporting P-type ATPases on the viability and virulence of Mtb. For this, recombination techniques were applied to construct mutants defective in the Mtb ctpF and ctpH genes that encode alkali/alkaline earth metal-transporting ATPases. Diverse functional analyses of these mutants demonstrated that both transporters are involved in Ca2+ efflux. Additionally, the mutant strains (MtbΔctpF and MtbΔctpH) showed hypersensitivity to oxidizing agents compared to the wild type strain (MtbWT), indicating a link between Ca2+ transport and the mechanism used by the bacillus to neutralize reactive species in the intraphagosomal environment. Moreover, the effect ctpF gene deletion on Mtb virulence was evaluated in cellular and animal infection models. Accordingly, this deletion generated a significant decrease in the replicative capacity of Mtb in murine alveolar macrophages of the MH-S cell line. Furthermore, a comparison of the virulence of MtbΔctpF and MtbWT strains through survival tests in BALB/c mice demonstrated that mice infected with the mutant strain showed a longer mean survival time, suggesting the attenuation of the deleted strain. Finally, the existence of a possible compensatory mechanism to counteract deficiencies in ion transport mediated by P-type ATPases in Mtb was evaluated. Indeed, the MtbΔctpF strain over-expresses the ctpH gene against toxic concentrations of Ca2+ and during in vitro infection processes. Similarly, the MtbΔctpH mutant over-expresses the ctpF gene under toxic concentrations of Ca2+, suggesting a possible compensatory activity between ctpF and ctpH in Mtb. This study demonstrates that Ca+2-ATPases are involved in the response to toxic substances, being essential for Mtb survival. Furthermore, CtpF is required for the intracellular proliferation of the mycobacteria, whereas its deletion attenuates the bacillus in an experimental model of pulmonary TB. Overall, CtpF is critical for Mtb virulence and can be an interesting attenuation target.Convocatoria nacional para el apoyo a proyectos de investigación y creación artística de la Universidad Nacional de Colombia 2017-2018 (Código 2010100-29088).Convocatoria nacional para el fomento de alianzas interdisciplinarias que articulen investigación, creación, extensión y formación en la Universidad Nacional de Colombia 2019-2021 (Código 2010100-29665).DoctoradoDoctor en Ciencias - BioquímicaPara el desarrollo de los objetivos propuestos en el presente trabajo, se estableció una estrategia experimental que incluyó herramientas bioquímicas, microbiológicas y de biología molecular.Hospedero-Patógenoxviii, 156 páginasapplication/pdfspa610 - Medicina y salud::616 - EnfermedadesMycobacterium tuberculosisMycobacterium tuberculosisATPasas tipo PCepas atenuadasTécnica de recombineríaCalcioP-type ATPaseAttenuated strainsMycobacterial recombineeringATPasas tipo P2 como blancos para la atenuación de Mycobacterium tuberculosis.P2-type ATPases as targets for the attenuation of Mycobacterium tuberculosis.Trabajo de grado - Doctoradoinfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/acceptedVersionhttp://purl.org/coar/resource_type/c_db06Texthttp://purl.org/redcol/resource_type/TDBogotá - Ciencias - Doctorado en Ciencias - BioquímicaDepartamento de QuímicaFacultad de CienciasBogotá, ColombiaUniversidad Nacional de Colombia - Sede BogotáN/AAgranoff, D. 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(2014) ‘New antituberculosis drugs, regimens, and adjunct therapies: Needs, advances, and future prospects’, The Lancet Infectious Diseases. doi: 10.1016/S1473-3099(13)70328-1.Implicación de CtpH, una ATPasa tipo P, en el transporte de metales alcalino/alcalinotérreos a través de la membrana plasmática de Mycobacterium tuberculosisAlianza estratégica para la evaluación preclínica de mutantes de Mycobacterium tuberculosis defectivos en ATPasas tipo P, con potencial vacunalDivisión de Investigación de Bogotá-DIBDepartamento Administrativo de Ciencia, Tecnología e Innovación (Colciencias)InvestigadoresPúblico generalLICENSElicense.txtlicense.txttext/plain; charset=utf-83964https://repositorio.unal.edu.co/bitstream/unal/80314/1/license.txtcccfe52f796b7c63423298c2d3365fc6MD51ORIGINAL1032383203.2021.pdf1032383203.2021.pdfTesis de Doctorado en Bioquímicaapplication/pdf78021777https://repositorio.unal.edu.co/bitstream/unal/80314/2/1032383203.2021.pdf6365e0d0233553885155258451f8a8f4MD52THUMBNAIL1032383203.2021.pdf.jpg1032383203.2021.pdf.jpgGenerated Thumbnailimage/jpeg4413https://repositorio.unal.edu.co/bitstream/unal/80314/3/1032383203.2021.pdf.jpgcfc074bfd74a19e8e84e0ea7080269ecMD53unal/80314oai:repositorio.unal.edu.co:unal/803142023-07-27 23:04:14.91Repositorio Institucional Universidad Nacional de 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GVyZWNob3MgZGUgYXV0b3IgcXVlIGNvbmxsZXZlIGxhIGRpc3RyaWJ1Y2nDs24gZGUgZXN0b3MgYXJjaGl2b3MgeSBtZXRhZGF0b3MuCkFsIGhhY2VyIGNsaWMgZW4gZWwgc2lndWllbnRlIGJvdMOzbiwgdXN0ZWQgaW5kaWNhIHF1ZSBlc3TDoSBkZSBhY3VlcmRvIGNvbiBlc3RvcyB0w6lybWlub3MuCgpVTklWRVJTSURBRCBOQUNJT05BTCBERSBDT0xPTUJJQSAtIMOabHRpbWEgbW9kaWZpY2FjacOzbiAyNy8yMC8yMDIwCg==

ATPasas tipo P2 como blancos para la atenuación de Mycobacterium tuberculosis.

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