Características microbiológicas asociadas a la virulencia de mutantes defectivos en los transportadores de membrana CtpF y MmpL7 de Mycobacterium tuberculosis

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dc.contributor.advisorSoto Ospina, Carlos Yesid
dc.contributor.advisorMaya Hoyos, Milena
dc.contributor.authorRicaurte, Sergio Nicolas
dc.contributor.researchgroupBioquímica y Biología Molecular de las Micobacterias
dc.coverage.countryColombia
dc.date.accessioned2026-02-12T15:36:45Z
dc.date.available2026-02-12T15:36:45Z
dc.date.issued2025
dc.descriptionIlustracionesspa
dc.description.abstractLa tuberculosis (TB) es una enfermedad infecciosa causada por el bacilo acido-alcohol resistente Mycobacterium tuberculosis (Mtb), una micobacteria que ataca principalmente a los pulmones, pero puede propagarse a otros órganos del hospedero. Esta enfermedad es considerada un problema de salud pública ocasionado principalmente por deficiencias en el diagnóstico, la baja eficacia de la única vacuna autorizada conocida como BCG, el surgimiento de cepas de Mtb resistentes y extremadamente resistentes a fármacos antituberculosos, y la coinfección con el virus de inmunodeficiencia humana (VIH). Para establecer estrategias efectivas de control contra la TB es relevante conocer los mecanismos moleculares que Mtb utiliza para ser un patógeno exitoso. En este sentido, es importante conocer los componentes estructurales del bacilo tuberculoso relacionados con su virulencia, tales como los sistemas de regulación, los lípidos de envoltura, los antígenos inmunodominantes, etc. Por lo tanto, conocer cómo las alteraciones de estos elementos podrían afectar las interacciones hospedero-patógeno permitirá conocer mejor los procesos implicados en la infección por TB, y desarrollar mejores estrategias de control. Estudios previos han demostrado que la deleción individual del gen ctpF de Mtb, que codifica para una ATPasa tipo P implicada en el eflujo de Ca2+ y en la respuesta frente al estrés oxidativo, así como también la del gen mmpL7 que codifica una proteína transmembranal involucrada en el transporte del lípido dimicocerosato de ftiocerol (PDIM), generan una atenuación de la virulencia de Mtb, evidenciando la importancia de estos transportadores en los procesos de infección. Por lo anterior, el objetivo del presente trabajo fue evaluar diferentes características microbiológicas asociadas con la virulencia de cepas mutantes de Mtb defectivas en los genes ctpF y mmpL7 (MtbH37Rv∆ctpF y MtbH37Rv∆mmpL7) comparadas con las exhibidas por la cepa salvaje MtbH37Rv. Inicialmente, se identificó que la deleción de los genes ctpF y mmpL7 altera la morfología de colonia, ocasionando que las cepas mutantes presenten una menor rugosidad de superficie. Además, las dos cepas mutantes poseen una menor hidrofobicidad relativa respecto a la cepa salvaje. Asimismo, para el caso de MtbH37Rv∆ctpF se evidenció una menor producción de biopelícula, la cual podría alterar las interacciones del bacilo con la superficie del medio, como lo observado con la alteración de su capacidad motil por deslizamiento. Adicionalmente, se evaluó el perfil cromatográfico de los lípidos PDIM y triacilglicéridos (TAG) de las cepas mutantes y la cepa salvaje, mediante cromatografía en capa fina (TLC). Así, la cepa MtbH37RvΔctpF mostró alteraciones en el perfil de los manósidos de fosfatidilinositol (PIM) y en los dimicolatos de trehalosa (TDM), conocidos como factor cuerda, los que están estrechamente relacionados con la organización estructural de la pared celular y la virulencia del bacilo tuberculoso. Por otro lado, en la cepa MtbH37RvΔmmpL7 se evidenció una acumulación intracelular de PDIM, lo que sugiere un defecto en su transporte hacia la superficie celular. Asimismo, al evaluar el perfil transcripcional de los genes asociados con la biosíntesis de PDIM, se observó una regulación negativa en la transcripción de los genes drrC, mas y lppX en las dos cepas mutantes, sugiriendo una disminución en la producción de este lípido en MtbH37RvΔctpF y MtbH37RvΔmmpL7. Por último, se estudió la producción de los antígenos: blanco antigénico de secreción temprana 6 kDa (ESAT-6), y la proteína de filtrado de cultivo 10 kDa (CFP-10) en las cepas mutantes. Se observó que para las dos cepas mutantes ambos son secretados al medio de cultivo, indicando que, a pesar de la atenuación sugerida por lo observado con las características asociadas con la virulencia mencionadas anteriormente, las cepas mutantes conservan su inmunogenicidad para desencadenar una respuesta en el sistema inmune del hospedero. En general, los resultados obtenidos en este estudio demuestran que las cepas MtbH37RvΔctpF y MtbH37RvΔmmpL7 presentan fenotipos relacionados con diversas características microbiológicas asociadas con la atenuación de Mtb. A pesar de esta atenuación, ambas cepas conservan su capacidad inmunomoduladora al secretar los antígenos ESAT-6 y CFP-10. Así, estos hallazgos destacan el potencial de las cepas mutantes evaluadas como candidatas para el diseño racional de una vacuna anti-TB basada en una cepa viva atenuada que incorpore ambas mutaciones. (Texto tomado de la fuente)spa
dc.description.abstractTuberculosis (TB) is an infectious disease caused by the acid-fast bacillus Mycobacterium tuberculosis (Mtb), a bacterium that primarily affects the lungs but can spread to other organs in the host. This disease is considered a public health problem mainly due to shortcomings in its diagnosis, the low efficacy of the only authorized vaccine (BCG), the emergence of Mtb strains resistant and extremely resistant to anti-tuberculosis drugs, and coinfection with human immunodeficiency virus (VIH). To establish effective control strategies against TB, it is essential to gain a better understanding of the molecular mechanisms employed by Mtb to thrive as an intracellular pathogen. In this regard, it is necessary to study the structural components of the bacillus related to its virulence, such as envelope lipids, immunodominant antigens, regulatory systems, etc. Therefore, investigating how alterations in these elements could affect host-pathogen interactions will shed light on the processes involved in TB infection and help develop improved approaches for its control. Previous studies have shown that deletion of the Mtb ctpF gene, which encodes a P-type ATPase involved in Ca2+ efflux and the response to oxidative stress, as well as mutation of the mmpL7 gene, which encodes a transmembrane protein involved in the transport of the phthiocerol dimycocerosate (PDIM) lipid, leads to an attenuation of pathogen virulence. This finding underscores the importance of these transporters in infection processes. Accordingly, the objective of this work was to evaluate various microbiological characteristics associated with the virulence of the mutant strains MtbH37Rv∆ctpF and MtbH37Rv∆mmpL7 and compare them to those exhibited by the wild-type strain MtbH37Rv. Initially, it was observed that deletion of the ctpF and mmpL7 genes in Mtb alters colony morphology, causing the mutant strains to have less surface roughness. In addition, both mutant strains exhibit lower relative hydrophobicity compared to the wild-type strain. Furthermore, in the case of MtbH37Rv∆ctpF, reduced biofilm production was observed, which could affect the bacillus’s interactions with the medium’s surface, as seen in the decreased sliding motility. Additionally, the chromatographic profiles of the glycolipids, PDIM, and triacylglycerides (TAG) of the mutant strains and the wild-type strain were assessed using thin-layer chromatography (TLC). Thus, the MtbH37Rv∆ctpF strain showed alterations in the profile of phosphatidylinositol mannosides (PIM) and trehalose dimycolates (TDM), also known as cord factor, which are closely related to the structural organization of the cell wall and the virulence of the tubercle bacillus. On the other hand, the MtbH37Rv∆mmpL7 strain showed intracellular accumulation of PDIM, suggesting a defect in its transport to the cell surface caused by the deletion of the mmpL7 gene in its genome. Likewise, when evaluating the transcriptional profile of the genes involved in PDIM biosynthesis, a negative regulation in the transcription of drrC, mas, and lppX was observed in both mutant strains, suggesting a decrease in the production of this lipid in MtbH37Rv∆ctpF and MtbH37Rv∆mmpL7, respectively. Finally, the production of two important antigens—early secreted antigenic target 6 kDa (ESAT-6) and culture filtrate protein 10 kDa (CFP-10)—was investigated in the mutant strains. It was found that both are secreted into the culture medium, indicating that despite the attenuation in virulence-related characteristics described above, the mutant strains maintain their immunogenicity to elicit a response in the host immune system. Overall, the results obtained in this study demonstrate that the MtbH37Rv∆ctpF and MtbH37Rv∆mmpL7 strains exhibit phenotypes linked to various microbiological characteristics associated with the attenuation of Mtb. Despite this attenuation, both strains preserve their immunomodulatory capacity by secreting the ESAT-6 and CFP-10 antigens. These findings therefore highlight the potential of the evaluated mutant strains as candidates for the rational design of a live attenuated anti-TB vaccine incorporating both mutations.eng
dc.description.degreelevelMaestría
dc.description.degreenameMagister en Microbiología
dc.format.extentxxvi, 174 páginas
dc.format.mimetypeapplication/pdf
dc.identifier.instnameUniversidad Nacional de Colombiaspa
dc.identifier.reponameRepositorio Institucional Universidad Nacional de Colombiaspa
dc.identifier.repourlhttps://repositorio.unal.edu.co/spa
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/89527
dc.language.isospa
dc.publisherUniversidad Nacional de Colombia
dc.publisher.branchUniversidad Nacional de Colombia - Sede Bogotá
dc.publisher.facultyFacultad de Ciencias
dc.publisher.placeBogotá, Colombia
dc.publisher.programBogotá - Ciencias - Maestría en Ciencias - Microbiología
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dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.rights.licenseReconocimiento 4.0 Internacional
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subject.ddc610 - Medicina y salud::616 - Enfermedades
dc.subject.decsMycobacterium tuberculosisspa
dc.subject.decsVacunas contra la tuberculosisspa
dc.subject.decsTuberculosis Vaccineseng
dc.subject.decsTuberculosis -- Genéticaspa
dc.subject.decsTuberculosis -- Geneticseng
dc.subject.decsFactores de Virulenciaspa
dc.subject.decsVirulence Factorseng
dc.subject.decsMycobacterium -- Crecimiento y desarrollospa
dc.subject.decsMycobacterium -- Growth & developmenteng
dc.subject.decsControl de infeccionesspa
dc.subject.decsInfection Controleng
dc.subject.proposalMycobacterium tuberculosisspa
dc.subject.proposalCepas vivas atenuadasspa
dc.subject.proposalCtpFeng
dc.subject.proposalMmpL7spa
dc.subject.proposalLípidos de envolturaspa
dc.subject.proposalATPasas tipo Pspa
dc.subject.proposalEnvelope lipidseng
dc.subject.proposalP-type ATPaseseng
dc.subject.proposalCFP-10eng
dc.subject.proposalESAT-6eng
dc.titleCaracterísticas microbiológicas asociadas a la virulencia de mutantes defectivos en los transportadores de membrana CtpF y MmpL7 de Mycobacterium tuberculosisspa
dc.title.translatedMicrobiological characteristics associated with virulence of defective mutants in the CtpF and MmpL7 membrane transporters of Mycobacterium tuberculosiseng
dc.typeTrabajo de grado - Maestría
dc.type.coarhttp://purl.org/coar/resource_type/c_bdcc
dc.type.coarversionhttp://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.contentText
dc.type.driverinfo:eu-repo/semantics/masterThesis
dc.type.redcolhttp://purl.org/redcol/resource_type/TM
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dcterms.audience.professionaldevelopmentEstudiantes
dcterms.audience.professionaldevelopmentInvestigadores
dcterms.audience.professionaldevelopmentMaestros
dcterms.audience.professionaldevelopmentPúblico general
dcterms.audience.professionaldevelopmentEspecializada
oaire.accessrightshttp://purl.org/coar/access_right/c_abf2

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