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Evaluación de la respuesta inmune frente a los potenciales candidatos a vacuna contra Plasmodium vivax PvRON2, Pv12, PvDBP y PvMSP1

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dc.contributor.advisorPatarroyo Gutierrez, Manuel Alfonso
dc.creatorLópez Santana, Sonia Carolina
dc.creator.degreeDoctor en Ciencias Biomédicas y Biológicas
dc.creator.degreeLevelDoctorado
dc.creator.degreetypeFull time
dc.date.accessioned2023-08-16T15:09:15Z
dc.date.available2023-08-16T15:09:15Z
dc.date.created2022-06-13
dc.descriptionLa malaria es una enfermedad infecciosa con altos índices de mortalidad alrededor del mundo. Ésta es causada por parásitos del género Plasmodium, siendo Plasmodium vivax la especie prevalente en el continente americano. En Colombia, para el año 2019 se reportaron 80.415 casos de malaria, de los cuales el 48.7% fueron causados por P. vivax, siendo los departamentos de Chocó, Antioquia, Nariño y Córdoba los de mayor incidencia. El control de esta enfermedad no se ha logrado, debido a la resistencia del parásito a los medicamentos empleados, a la resistencia a los insecticidas adquirida por el vector y a las políticas de salud deficientes. Ante esta situación, la vacunación es considerada como la mejor alternativa de prevención y con mayor potencial para reducir la morbilidad y mortalidad en las poblaciones afectadas. Dada la dificultad para realizar cultivos continuos in vitro de P. vivax, la mayor parte de la investigación en malaria se ha enfocado en P. falciparum. A pesar de esto, en los últimos años, la Fundación Instituto de Inmunología de Colombia (FIDIC) ha logrado caracterizar varias proteínas de P. vivax como posibles candidatos a vacuna; sin embargo, aún se desconoce la capacidad de la mayoría de estas proteínas, y de los epítopes derivados de ellas, para ser reconocidos por componentes de la respuesta inmune humoral y celular. Con el fin de profundizar en la caracterización de proteínas y/o péptidos como potenciales candidatos, la primera fase del estudio planteó la realización de ensayos de antigenicidad in vitro con muestras de individuos expuestos a la infección natural en áreas endémicas de Colombia. Para esto, los epítopes B y T fueron seleccionados in silico y la elección de epítopes T fue definida con ensayos de unión in vitro a moléculas HLA-DRβ, obtenidas a partir de líneas celulares linfoblastoides B humanas. Los individuos fueron elegidos de acuerdo con la expresión de alelos HLA-DRβ1* de frecuencia intermedia en las poblaciones blanco para una vacuna contra la malaria (HLA-DRβ1*04, *07, *11 y *13). Durante la segunda fase de este estudio, se evaluó la inmunogenicidad in vitro de péptidos nativos y modificados derivados de las proteínas. Para esto, se emplearon linfocitos T CD4+ vírgenes de individuos sanos con restricción a los alelos HLA-DRβ1* antes mencionados, estimulados con células dendríticas como células presentadoras de antígeno profesionales. Finalmente, se estableció que existe una correlación entre la capacidad de unión a moléculas HLA-DR y la inmunogenicidad de los péptidos modificados derivados de proteínas de P. vivax. Los resultados de este estudio generaron datos relevantes para futuros estudios de inmunogenicidad y protección en modelos experimentales, encaminados a la comprensión de los mecanismos de la respuesta inmune frente a P. vivax y a la generación de una vacuna efectiva contra la malaria.
dc.description.abstractMalaria is an infectious disease with high mortality rates around the world. This is caused by parasites of the genus Plasmodium, Plasmodium vivax being the prevalent species in the American continent. In Colombia, for the year 2019, 80,415 cases of malaria were reported, of which 48.7% were caused by P. vivax, with the departments of Chocó, Antioquia, Nariño, and Córdoba having the highest incidence. Control of this disease has not been achieved due to resistance of the parasite to the drugs used, resistance to insecticides acquired by the vector, and poor health policies. Given this situation, vaccination is considered the best prevention alternative and with the greatest potential to reduce morbidity and mortality in affected populations. Given the difficulty in performing continuously in vitro cultures of P. vivax, most malaria research has focused on P. falciparum. Despite this, in recent years, the Fundación Instituto de Inmunología de Colombia (FIDIC) has succeeded in characterizing several P. vivax proteins as potential vaccine candidates; however, the ability of most of these proteins, and of the epitopes derived from them, to be recognized by components of the humoral and cellular immune response is still unknown. In order to deepen the characterization of proteins and/or peptides as potential candidates, the first phase of the study proposed carrying out in vitro antigenicity assays with samples from individuals exposed to natural infection in endemic areas of Colombia. For this, the B and T epitopes were selected in silico and the choice of T epitopes was defined with in vitro binding assays to HLA-DRβ molecules, obtained from human B lymphoblastoid cell lines. Individuals were chosen according to the expression of intermediate frequency HLA-DRβ1* alleles in the target populations for a malaria vaccine (HLA-DRβ1*04, *07, *11, and *13). During the second phase of this study, the in vitro immunogenicity of native and modified peptides derived from the proteins was evaluated. For this, naïve CD4+ T lymphocytes from healthy individuals with restriction to the aforementioned HLA-DRβ1* alleles, stimulated with dendritic cells as professional antigen-presenting cells, were used. Finally, it was established that there is a correlation between the ability to bind to HLA-DR molecules and the immunogenicity of the modified peptides derived from P. vivax proteins. The results of this study generated relevant data for future immunogenicity and protection studies in experimental models, aimed at understanding the mechanisms of the immune response against P. vivax and generating an effective vaccine against malaria.
dc.description.sponsorshipColciencias
dc.format.extent195
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.48713/10336_40688
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/40688
dc.language.isospa
dc.publisherUniversidad del Rosario
dc.publisher.departmentEscuela de Medicina y Ciencias de la Salud
dc.publisher.programDoctorado en Ciencias Biomédicas y Biológicas
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dc.source.instnameinstname:Universidad del Rosario
dc.source.reponamereponame:Repositorio Institucional EdocUR
dc.subjectMalaria
dc.subjectPlasmodium vivax
dc.subjectHLA-DR
dc.subjectPéptidos sintéticos
dc.subjectRespuesta inmune
dc.subjectVacunas
dc.subject.keywordMalaria
dc.subject.keywordPlasmodium vivax
dc.subject.keywordHLA-DR
dc.subject.keywordSynthetic peptides
dc.subject.keywordImmune response
dc.subject.keywordVaccines
dc.titleEvaluación de la respuesta inmune frente a los potenciales candidatos a vacuna contra Plasmodium vivax PvRON2, Pv12, PvDBP y PvMSP1
dc.title.TranslatedTitleEvaluation of the immune response against potential vaccine candidates against Plasmodium vivax PvRON2, Pv12, PvDBP, and PvMSP1
dc.typemasterThesis
dc.type.documentTesis
dc.type.hasVersioninfo:eu-repo/semantics/acceptedVersion
dc.type.spaTesis
local.department.reportEscuela de Medicina y Ciencias de la Salud
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Doctorado en Ciencias Biomédicas y Biológicas