Evaluación de la respuesta inmune estimulada por péptidos de alta capacidad de unión a moléculas H2-IEd, en modelo murino.

...

Autores:
Rodríguez Obediente, Kewin Jair
Tipo de recurso:
Fecha de publicación:
2023
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/84062
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/84062
https://repositorio.unal.edu.co/
Palabra clave:
Cultivo in vitro
Inmunología
Antígenos
In vitro culture
Immunology
Antigens
Selección purificante
Epítopos B
Epítopos T
Péptidos quiméricos
Inmunogenicidad
Plasmodium yoelii
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openAccess
License
Atribución-NoComercial-SinDerivadas 4.0 Internacional
id UNACIONAL2_e36021eddb6a566f8324c13415a6a436
oai_identifier_str oai:repositorio.unal.edu.co:unal/84062
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Evaluación de la respuesta inmune estimulada por péptidos de alta capacidad de unión a moléculas H2-IEd, en modelo murino.
dc.title.translated.eng.fl_str_mv Evaluation of the immune response stimulated by peptides with high binding capacity to H2-IEd molecules in a murine model.
title Evaluación de la respuesta inmune estimulada por péptidos de alta capacidad de unión a moléculas H2-IEd, en modelo murino.
spellingShingle Evaluación de la respuesta inmune estimulada por péptidos de alta capacidad de unión a moléculas H2-IEd, en modelo murino.
Cultivo in vitro
Inmunología
Antígenos
In vitro culture
Immunology
Antigens
Selección purificante
Epítopos B
Epítopos T
Péptidos quiméricos
Inmunogenicidad
Plasmodium yoelii
title_short Evaluación de la respuesta inmune estimulada por péptidos de alta capacidad de unión a moléculas H2-IEd, en modelo murino.
title_full Evaluación de la respuesta inmune estimulada por péptidos de alta capacidad de unión a moléculas H2-IEd, en modelo murino.
title_fullStr Evaluación de la respuesta inmune estimulada por péptidos de alta capacidad de unión a moléculas H2-IEd, en modelo murino.
title_full_unstemmed Evaluación de la respuesta inmune estimulada por péptidos de alta capacidad de unión a moléculas H2-IEd, en modelo murino.
title_sort Evaluación de la respuesta inmune estimulada por péptidos de alta capacidad de unión a moléculas H2-IEd, en modelo murino.
dc.creator.fl_str_mv Rodríguez Obediente, Kewin Jair
dc.contributor.advisor.none.fl_str_mv Díaz Arévalo, Diana
dc.contributor.author.none.fl_str_mv Rodríguez Obediente, Kewin Jair
dc.contributor.projectleader.none.fl_str_mv Manuel Alfonso Patarroyo Gutierrez
dc.contributor.researchgroup.spa.fl_str_mv Biología Molecular e Inmunología
dc.contributor.orcid.spa.fl_str_mv https://orcid.org/0000-0002-6181-9154
dc.subject.lemb.spa.fl_str_mv Cultivo in vitro
Inmunología
Antígenos
topic Cultivo in vitro
Inmunología
Antígenos
In vitro culture
Immunology
Antigens
Selección purificante
Epítopos B
Epítopos T
Péptidos quiméricos
Inmunogenicidad
Plasmodium yoelii
dc.subject.lemb.eng.fl_str_mv In vitro culture
Immunology
Antigens
dc.subject.proposal.spa.fl_str_mv Selección purificante
Epítopos B
Epítopos T
Péptidos quiméricos
Inmunogenicidad
Plasmodium yoelii
description ...
publishDate 2023
dc.date.accessioned.none.fl_str_mv 2023-06-23T18:28:00Z
dc.date.available.none.fl_str_mv 2023-06-23T18:28:00Z
dc.date.issued.none.fl_str_mv 2023
dc.type.spa.fl_str_mv Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv Text
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/TM
status_str acceptedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unal.edu.co/handle/unal/84062
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/84062
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
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Arévalo-Pinzón G, Bermúdez M, Hernández D, Curtidor H, Patarroyo MA. Plasmodium vivax ligand-receptor interaction: PvAMA-1 domain I contains the minimal regions for specific interaction with CD71+ reticulocytes. Scientific reports. 2017;7(1):1-13.
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dc.rights.license.spa.fl_str_mv Atribución-NoComercial-SinDerivadas 4.0 Internacional
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rights_invalid_str_mv Atribución-NoComercial-SinDerivadas 4.0 Internacional
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dc.format.extent.spa.fl_str_mv 87 páginas
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dc.publisher.spa.fl_str_mv Universidad Nacional de Colombia
dc.publisher.program.spa.fl_str_mv Bogotá - Ciencias - Maestría en Ciencias - Microbiología
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
institution Universidad Nacional de Colombia
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spelling Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Díaz Arévalo, Diana4b9a1ebb1633a8c2defe6148569778fcRodríguez Obediente, Kewin Jair37bb1f00483c3f3e38356be032a1bf8bManuel Alfonso Patarroyo GutierrezBiología Molecular e Inmunologíahttps://orcid.org/0000-0002-6181-91542023-06-23T18:28:00Z2023-06-23T18:28:00Z2023https://repositorio.unal.edu.co/handle/unal/84062Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/...La complejidad biológica de Plasmodium vivax ha restringido el desarrollo del cultivo in vitro para la caracterización de antígenos involucrados en la invasión a eritrocitos y su relevancia inmunológica. El modelo murino se propone como una alternativa en la búsqueda de candidatos terapéuticos, ya que, Plasmodium yoelii utiliza proteínas homólogas para los mecanismos de invasión. La proteína AMA-1 es vital para el proceso de invasión del parásito al eritrocito, considerándose una importante diana para el control de la infección. El presente estudio, como prueba de concepto, se centró en la caracterización de la respuesta inmune estimulada por constructos peptídicos compuestos por epítopos B de la proteína PyAMA-1 y epítopos T optimizados in silico para el anclaje a moléculas H2-IEd, probados en ratones BALB/c. Para la selección de epítopos B antimaláricos, se realizó un análisis de restricción funcional por fuerzas evolutivas in silico. Encontramos que pyama1 presenta dos regiones altamente conservadas entre las especies (>70%) bajo selección negativa. Se evaluaron catorce péptidos sintéticos que cubrían el total de ambas regiones conservadas, identificando 5 péptidos de PyAMA-1 con alta unión específica (HABP, del inglés High Activity Binding Peptide) a eritrocitos murinos. Mediante ensayos in vitro se evaluó el perfil funcional de los HABPs, sugiriendo que los péptidos 42681 y 42904 fueron capaces de inhibir la invasión y restringir el desarrollo intraeritrocítico de P. yoelii y, además, mostraron capacidad antigénica frente a sueros obtenidos de ratones infectados experimentalmente. Mediante un análisis bioinformático robusto, se realizó el diseño y optimización de los epítopos B seleccionados, a través de la articulación de un epítopo T completamente artificial y se evaluó su unión in vitro a moléculas H2-IEd. Los epítopos quiméricos B-T 43643 y 43644 presentaron perfiles de unión superiores a 50% a moléculas de MHC murino. Además, nuestros constructos potenciaron la respuesta humoral en ratones BALB/c, comparados con los péptidos nativos, y a su vez, mostraron anticuerpos IgG1 e IgG2 en sueros. Estas quimeras peptídicas fueron capaces de inducir una respuesta proliferativa y la diferenciación de células T de memoria CD4+ CD44+ CD62L+, generando una producción coordinada de TNFα, como mediador de la eliminación del parásito durante la infección temprana de P. yoelii. Este trabajo propone la quimerización de epítopos B y epítopos T como una estrategia para el diseño de candidatos peptídicos inmunogénicos para el desarrollo de una vacuna sintética multiepítopo – multiestadio contra la malaria. (Texto tomado de la fuente)ilustraciones, fotografías a colorThe biological complexity of Plasmodium vivax has limited developing an in vitro culture for the characterization of antigens involved in erythrocyte invasion and their immunological relevance. The murine model is proposed as an alternative in the search for therapeutic candidates since Plasmodium yoelii uses homologous proteins for invasion. The AMA-1 protein is vital for the parasite invasion of the erythrocyte and is considered an important target for malaria control. The present study, as a proof of concept, focused on the characterization of the immune response stimulated by peptide constructs made of B epitopes of the PyAMA-1 protein and T epitopes optimized in silico for anchoring to H2-IEd molecules, tested in BALB/c mice. For the selection of antimalarial B epitopes, an in silico evolutionary force functional constraint analysis was performed. We found that pyama1 exhibits two highly conserved regions among species (>70%) under negative selection. Fourteen synthetic peptides covering both conserved regions were evaluated, identifying 5 PyAMA-1 peptides displaying high specific binding (High Activity Binding Peptides or HABPs) to murine erythrocytes. In vitro assays evaluated the functional profile of the HABPs, suggesting that peptides 42681 and 42904 were able to inhibit invasion and restrict intraerythrocytic development of P. yoelii and, in addition, showed antigenic capacity when tested with sera obtained from experimentally infected mice. By means of a robust bioinformatics analysis, the design and optimization of the selected B epitopes was achieved by linking them to a completely artificial T epitope and assessing their in vitro binding to H2-IEd molecules. The chimeric B-T epitopes 43643 and 43644 showed binding profiles higher than 50% to murine MHC molecules. Furthermore, our constructs enhanced the humoral response in BALB/c mice compared to native peptides, and increased IgG1 and IgG2a antibodies in sera. These peptide chimeras were able to induce a proliferative response and differentiation of CD4+ CD44+ CD62L+ memory T cells, generating a coordinated production of TNFα, as a mediator of parasite clearance during early P. yoelii infection. 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Proceedings of the National Academy of Sciences. 1986;83(11):3968-71.Cultivo in vitroInmunologíaAntígenosIn vitro cultureImmunologyAntigensSelección purificanteEpítopos BEpítopos TPéptidos quiméricosInmunogenicidadPlasmodium yoeliiFundación Instituto de Inmunología de Colombia - FIDICInvestigadoresLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/84062/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1124036814.2023.pdf1124036814.2023.pdfTesis de Maestría en Ciencias - Microbiologíaapplication/pdf3383419https://repositorio.unal.edu.co/bitstream/unal/84062/2/1124036814.2023.pdf1ee89014164dbd67c8bf27bcb236c2feMD52THUMBNAIL1124036814.2023.pdf.jpg1124036814.2023.pdf.jpgGenerated Thumbnailimage/jpeg5778https://repositorio.unal.edu.co/bitstream/unal/84062/3/1124036814.2023.pdf.jpg3cfcea36aab1a241c803284808b363ddMD53unal/84062oai:repositorio.unal.edu.co:unal/840622023-08-09 23:04:06.739Repositorio Institucional Universidad Nacional de Colombiarepositorio_nal@unal.edu.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