Caracterización de la respuesta de linfocitos T-CD4+ de memoria específicos para péptidos derivados de proteínas de Leishmania como potenciales candidatos a vacuna

ilustraciones, gráficas, tablas

Autores:
Flórez Martínez, Magda Melissa
Tipo de recurso:
Doctoral thesis
Fecha de publicación:
2021
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/80814
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/80814
https://repositorio.unal.edu.co/
Palabra clave:
570 - Biología
Antígenos
Leishmaniasis
Péptidos
Antigens
Leishmaniasis
Peptides
Leishmaniasis
Vacunología reversa
Péptidos sintéticos
Humanos
Células de memoria
In vivo
Vacunas
Leishmaniasis
vaccines
Reverse vaccinology
Synthetic peptides
Human
Memory cells
In vivo
Rights
openAccess
License
Reconocimiento 4.0 Internacional
id UNACIONAL2_38e06be0e10098c1d044c07b6f09cb43
oai_identifier_str oai:repositorio.unal.edu.co:unal/80814
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Caracterización de la respuesta de linfocitos T-CD4+ de memoria específicos para péptidos derivados de proteínas de Leishmania como potenciales candidatos a vacuna
dc.title.translated.eng.fl_str_mv Characterization of the memory T-CD4+ lymphocyte response specific for peptides derived from Leishmania proteins as potential vaccine candidates
title Caracterización de la respuesta de linfocitos T-CD4+ de memoria específicos para péptidos derivados de proteínas de Leishmania como potenciales candidatos a vacuna
spellingShingle Caracterización de la respuesta de linfocitos T-CD4+ de memoria específicos para péptidos derivados de proteínas de Leishmania como potenciales candidatos a vacuna
570 - Biología
Antígenos
Leishmaniasis
Péptidos
Antigens
Leishmaniasis
Peptides
Leishmaniasis
Vacunología reversa
Péptidos sintéticos
Humanos
Células de memoria
In vivo
Vacunas
Leishmaniasis
vaccines
Reverse vaccinology
Synthetic peptides
Human
Memory cells
In vivo
title_short Caracterización de la respuesta de linfocitos T-CD4+ de memoria específicos para péptidos derivados de proteínas de Leishmania como potenciales candidatos a vacuna
title_full Caracterización de la respuesta de linfocitos T-CD4+ de memoria específicos para péptidos derivados de proteínas de Leishmania como potenciales candidatos a vacuna
title_fullStr Caracterización de la respuesta de linfocitos T-CD4+ de memoria específicos para péptidos derivados de proteínas de Leishmania como potenciales candidatos a vacuna
title_full_unstemmed Caracterización de la respuesta de linfocitos T-CD4+ de memoria específicos para péptidos derivados de proteínas de Leishmania como potenciales candidatos a vacuna
title_sort Caracterización de la respuesta de linfocitos T-CD4+ de memoria específicos para péptidos derivados de proteínas de Leishmania como potenciales candidatos a vacuna
dc.creator.fl_str_mv Flórez Martínez, Magda Melissa
dc.contributor.advisor.spa.fl_str_mv Delgado Murcia, Lucy Gabriela
dc.contributor.author.spa.fl_str_mv Flórez Martínez, Magda Melissa
dc.contributor.researchgroup.spa.fl_str_mv Grupo de Investigación en Inmunotoxicología
dc.subject.ddc.spa.fl_str_mv 570 - Biología
topic 570 - Biología
Antígenos
Leishmaniasis
Péptidos
Antigens
Leishmaniasis
Peptides
Leishmaniasis
Vacunología reversa
Péptidos sintéticos
Humanos
Células de memoria
In vivo
Vacunas
Leishmaniasis
vaccines
Reverse vaccinology
Synthetic peptides
Human
Memory cells
In vivo
dc.subject.decs.spa.fl_str_mv Antígenos
Leishmaniasis
Péptidos
dc.subject.decs.eng.fl_str_mv Antigens
Leishmaniasis
Peptides
dc.subject.proposal.spa.fl_str_mv Leishmaniasis
Vacunología reversa
Péptidos sintéticos
Humanos
Células de memoria
In vivo
Vacunas
dc.subject.proposal.eng.fl_str_mv Leishmaniasis
vaccines
Reverse vaccinology
Synthetic peptides
Human
Memory cells
In vivo
description ilustraciones, gráficas, tablas
publishDate 2021
dc.date.issued.none.fl_str_mv 2021-12-14
dc.date.accessioned.none.fl_str_mv 2022-01-31T16:41:48Z
dc.date.available.none.fl_str_mv 2022-01-31T16:41:48Z
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/80814
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/80814
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 Bireme
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spelling Reconocimiento 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Delgado Murcia, Lucy Gabriela5a5d74a7f279e35695f243a887783c55Flórez Martínez, Magda Melissadac967e0beb39ac616b9f4c211cafbfcGrupo de Investigación en Inmunotoxicología2022-01-31T16:41:48Z2022-01-31T16:41:48Z2021-12-14https://repositorio.unal.edu.co/handle/unal/80814Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, gráficas, tablasLa leishmaniasis es una enfermedad parasitaria tropical, desatendida y ampliamente distribuida en el mundo. Hace parte de las enfermedades zoonóticas, transmitidas por vectores que genera alrededor de 1 millón de casos anualmente, siendo la forma Leishmaniasis cutánea, la presentación clínica más prevalente. Se ha desarrollado múltiples frentes para la intervención de esta enfermedad como el control de vectores, el desarrollo de productos terapéuticos y vacunas. Sin embargo, ésta última, aunque costo efectiva comparada con las demás estrategias, si avance es muy limitado hacia el licenciamiento de prototipos vacunales para uso en humanos. Este trabajo se enfocó en la identificación de epítopes naturales de Leishmania spp., es decir, aquellas secuencias que fueron reconocidas como antígenos y que indujeron respuesta inmune en la infección natural del parásito en humanos (especialmente en aquellos resistentes a la enfermedad) y su validación como candidatos a vacuna en un modelo murino. Para cumplir el objetivo, inicialmente se identificaron de péptidos derivados de proteínas inmunogénicas de Leishmania spp por medio de una estrategia in sílico y después de su síntesis, su evaluación en humanos mediante el uso de células dendríticas como Células Presentadoras de Antígenos –APCs- derivadas de sangre periférica, a partir de individuos sin exposición y expuestos al parásito, en distintos estadios de la enfermedad. Posteriormente, y luego de seleccionar in vitro los péptidos inmunogénicos, se identificaron el perfil de células de memoria específicas para los antígenos de interés (en los voluntarios humanos) y finalmente se evaluó su inmunogenicidad in vivo en el modelo murino BALB/c. Como resultados obtuvimos a partir de más de 1400 secuencias candidatas, la identificación de 11 péptidos provenientes de 3 proteínas de Leishmania spp. (LACK, STI1 y LEIF) mediante el empleo de 3 herramientas bioinformáticas simultáneamente. A partir de estos 11 péptidos identificamos que STI41, STI46 y STI43 generan linfoproliferación en PBMCs derivados de humanos naturalmente expuestos al parásito, además de secretar citoquinas del perfil inflamatorio (TNFα e IFNγ) los dos primeros y del perfil regulador (IL- 10), el último. Posteriormente, identificamos que el alelo HLA-DRβ1 04:05 podría estar asociado a la susceptibilidad de los individuos a la leishmaniasis, además que aquellos resistentes a la misma generan células TCM y Teff frente a antígenos del parásito y que los péptidos STI41 y STI46 generan células TSCM y Teff en los mismos. Finalmente, observamos en un modelo de leishmaniasis cutánea por Leishmania panamensis (L. panamensis) en ratones BALB/c que la inmunización con el péptido STI41 logró la reducción de las úlceras a tamaños más pequeños respecto a los ratones control y producción de IFNγ y TNFα en esplenocitos ex vivo, al igual que el péptido STI43 cuyo uso generó lesiones más pequeñas, pero en menor medida que STI41, junto con la bajoregulación de IL-4 e IFNγ. Concluimos que la estrategia de vacunología reversa permitió el estudio en un número reducido de candidatos (11 de 1483) que tras la experimentación in vitro confirmamos para tres de estos su caracterización como epítopes de células T en humanos naturalmente expuestos a la leishmaniasis. Dos secuencias STI41 y STI43 generaron una mejor resolución de la infección por L. panamensis en ratones BALB/c por lo que podrían ser valiosos candidatos a ser incluidos en una futura vacuna para la leishmanisis. (Texto tomado de la fuente).Leishmaniasis is a neglected tropical disease cause by Leishmania parasite, distributed worldwide. It is a zoonosis and vectorborne disease that causes around 1 million cases each year, with Cutaneous leishmanisis as the most prevalent clinical form. Multiple strategies have been developed to manage the disease as vector control, treatment, and vaccine development, however, the last one, although cost-effective compared with other strategies, so far there aren’t any licensed vaccines for use in humans. This work was focused on the identification of natural Leishmania spp. Epitopes, it means, those sequences that were identified as antigens and that generated immune response against the parasite in humans, especially in those resistant to the disease and its validation as vaccine candidates in a murine model. In order to achieve the aim, first, several peptides were identified from immunogenic Leishmania proteins, using in sílico analyses, and after, we selected sequences and synthetized and evaluated in PBMCs, using dendritic cells a APCs from human volunteers naturally exposed or not to the parasite. Next, memory cells profile were identified for these peptides chosen in the previous step, and finally selected sequences were assessed in vivo. As results, we obtained from more than 1400 candidate sequences, the identification of 11 peptides from 3 proteins of Leishmania spp. (LACK, STI1, and LEIF) by using three bioinformatics tools, simultaneously. From these 11 peptides, we identified that STI41, STI46, and STI43 generate lymphoproliferation in PBMCs derived from humans naturally exposed to the parasite. In addition, we detected cytokine secretion of the first two inflammatory profiles (TNFα e IFNγ) and the last one of the regulatory profile (IL-10). Subsequently, we identified that the HLA-DRβ1 04:05 allele could be associated with the susceptibility of individuals to leishmaniasis, in addition, that those Resistant generate TCM and Teff cells against parasite antigens and that the STI41 and STI46 peptides generate TSCM and Teff cells in them. Finally, we observed in a model of cutaneous leishmaniasis caused by L. panamensis in BALB/c mice, secondary to immunization with the STI41 peptide, a reduction of ulcers with smaller sizes than the control mice and production of IFNγ and TNFα in splenocytes ex vivo; whereas the immunization with STI43 peptide induced smaller lesions but to a lesser extent than STI41, together with the down-regulation of IL-4 and IFNγ. We conclude that the reverse vaccinology strategy allowed the study in a small number of candidates (11 out of 1483) which, after in vitro and ex vivo experimentation, confirmed for three of them their behavior as T-cell epitope in humans naturally exposed to leishmaniasis and that of these, two sequences STI41 and STI43 generate a better resolution of infection by L. panamensis in BALB/c mice, justifying the potential use as vaccine candidates to be included in a future formulation toward the prophylactic control of leishmanisis.Incluye anexosDoctoradoDoctor en BiotecnologíaBiotecnología en salud humana y animalxiii, 114 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Ciencias - Doctorado en BiotecnologíaInstituto de Biotecnología (IBUN)Facultad de CienciasBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá570 - BiologíaAntígenosLeishmaniasisPéptidosAntigensLeishmaniasisPeptidesLeishmaniasisVacunología reversaPéptidos sintéticosHumanosCélulas de memoriaIn vivoVacunasLeishmaniasisvaccinesReverse vaccinologySynthetic peptidesHumanMemory cellsIn vivoCaracterización de la respuesta de linfocitos T-CD4+ de memoria específicos para péptidos derivados de proteínas de Leishmania como potenciales candidatos a vacunaCharacterization of the memory T-CD4+ lymphocyte response specific for peptides derived from Leishmania proteins as potential vaccine candidatesTrabajo de grado - Doctoradoinfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/acceptedVersionhttp://purl.org/coar/resource_type/c_db06Texthttp://purl.org/redcol/resource_type/TDBireme1. 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Parasites & vectors. 2020;13(1).Público generalORIGINAL1096948309.2021.pdf1096948309.2021.pdfTesis de Doctorado en Biotecnologíaapplication/pdf9868913https://repositorio.unal.edu.co/bitstream/unal/80814/3/1096948309.2021.pdf5c393b9d99c04283fcefcb77b7b9bc7fMD53LICENSElicense.txtlicense.txttext/plain; charset=utf-84074https://repositorio.unal.edu.co/bitstream/unal/80814/4/license.txt8153f7789df02f0a4c9e079953658ab2MD54THUMBNAIL1096948309.2021.pdf.jpg1096948309.2021.pdf.jpgGenerated Thumbnailimage/jpeg3902https://repositorio.unal.edu.co/bitstream/unal/80814/5/1096948309.2021.pdf.jpg13518bce7ad289ff072c9cdb1bc072d0MD55unal/80814oai:repositorio.unal.edu.co:unal/808142024-08-02 23:10:43.448Repositorio Institucional Universidad Nacional de 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EVESURBIFBPUiBMQSBTRUNSRVRBUsONQSBHRU5FUkFMLiAqTEEgVEVTSVMgQSBQVUJMSUNBUiBERUJFIFNFUiBMQSBWRVJTScOTTiBGSU5BTCBBUFJPQkFEQS4gCgpBbCBoYWNlciBjbGljIGVuIGVsIHNpZ3VpZW50ZSBib3TDs24sIHVzdGVkIGluZGljYSBxdWUgZXN0w6EgZGUgYWN1ZXJkbyBjb24gZXN0b3MgdMOpcm1pbm9zLiBTaSB0aWVuZSBhbGd1bmEgZHVkYSBzb2JyZSBsYSBsaWNlbmNpYSwgcG9yIGZhdm9yLCBjb250YWN0ZSBjb24gZWwgYWRtaW5pc3RyYWRvciBkZWwgc2lzdGVtYS4KClVOSVZFUlNJREFEIE5BQ0lPTkFMIERFIENPTE9NQklBIC0gw5psdGltYSBtb2RpZmljYWNpw7NuIDE5LzEwLzIwMjEK

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