Publication: Inmunidad a la malaria letal en modelos murinos : adquisición espontánea o mediada por tratamiento quimioterapéutico.
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2013-11-05
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Universidad Complutense de Madrid
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Abstract
La malaria es uno de los problemas sanitarios más importantes en el mundo. La incompleta respuesta inmune a la malaria, junto con la falta de una vacuna eficaz y el aumento de la resistencia de los parásitos a los fármacos en uso dificultan el control de la malaria. La inmunidad que se adquiere de forma natural frente a la infección por Plasmodium falciparum en humanos es de corta duración y solo la adquieren individuos adultos tras años de repetidas infecciones, con la excepción de mujeres embarazadas. Con el objetivo de examinar la respuesta inmune a la malaria adquirida tras tratamiento en modelos de ratón utilizamos borrelidina que inhibe treonil-ARNt sintetasas. En el modelo de malaria letal por Plasmodium yoelii yoelii en ratones BALB/c, el antibiótico borrelidina protege al 100% de los ratones y produce la sincronización del parásito en el estadio de trofozoíto. La borrelidina actúa sobre P. falciparum, induciendo in vitro un efecto parcialmente parasitostático en el estadio de anillo y parasiticida en los estadios maduros.
Por otro lado, para examinar la respuesta inmune a la malaria adquirida naturalmente, utilizamos un nuevo modelo animal. Los ratones no consanguíneos ICR que, infectados con P. yoelii letal, muestran tres evoluciones clínicas. El peor pronóstico se relaciona con un aumento de células de la inmunidad innata, células CD4+CD25+ y células B inmaduras en circulación y se acompaña, en el momento más crítico de la infección, de una sobreproducción citoquinas. Los ratones supervivientes se caracterizan por el incremento de células activadas T y B. En los individuos supervivientes, una sola infección es capaz de generar células B de memoria que se mantienen durante más de un año en bazo.
Por último, los ratones BALB/c e ICR que sobreviven, por tratamiento quimioterapéutico o espontáneamente respectivamente, a la infección tras mostrar una parasitemia, desarrollan una respuesta humoral protectora a largo plazo contra sucesivas reinfecciones homólogas. La pérdida de contacto parásito-hospedador que se produce entre reinfecciones disminuye la avidez de los anticuerpos por su antígeno, así como la variedad de proteínas antigénicas de Plasmodium reconocidas por los anticuerpos.
Malaria is one of the most important global health problems. The incomplete immune response to malaria, together with the lack of a licensed vaccine and the spread of drug resistant parasites hinder malaria control. Natural acquired immunity against Plasmodium falciparum can be acquired only after years of repeated infection in adults, but generally not in pregnant women, and does not persist over long periods of time. The first aim of this project was to study the immune response against malaria after antimalarial treatment in a mouse model. We used the antibiotic borrelidin which is an inhibitor of threonil tRNA synthetase. In the model of lethal malaria caused by P. yoelii in BALB/c mice, the antibiotic borrelidin protects to 100% of mice and promotes the parasite synchronization at the trophozoite stage. Borrelidin has an in vitro activity against P. falciparum which induces a partial static effect in the ring stage and a cidal effect in mature stages. On the other hand, to examine the immune response naturally acquired against malaria, we used a new mouse model. The infection of non-congenic ICR mouse strain with lethal P. yoelii leads to three malaria clinical evolution. The worst prognosis is associated with the increase in the circulation of innate immune cells, CD4+CD25+ cells and immature B cells and is accompanied by overproduction of cytokines in the most critical time point of the infection. Surviving mice are characterized by the increase in circulating activated T cells and B cells at the end of the infection. In surviving mice, a single infection is able to generate memory B cells that are maintained for more than a year in spleen. Finally, mice which survive, after chemotherapy or spontaneously, to the infection after showing a parasitemia, develop a long-term protective humoral response against reinfections. The absence of parasite exposure between reinfections decreases both the antibody avidity for it antigen and the repertoire of Plasmodium antigens recognized by the antibodies.
Malaria is one of the most important global health problems. The incomplete immune response to malaria, together with the lack of a licensed vaccine and the spread of drug resistant parasites hinder malaria control. Natural acquired immunity against Plasmodium falciparum can be acquired only after years of repeated infection in adults, but generally not in pregnant women, and does not persist over long periods of time. The first aim of this project was to study the immune response against malaria after antimalarial treatment in a mouse model. We used the antibiotic borrelidin which is an inhibitor of threonil tRNA synthetase. In the model of lethal malaria caused by P. yoelii in BALB/c mice, the antibiotic borrelidin protects to 100% of mice and promotes the parasite synchronization at the trophozoite stage. Borrelidin has an in vitro activity against P. falciparum which induces a partial static effect in the ring stage and a cidal effect in mature stages. On the other hand, to examine the immune response naturally acquired against malaria, we used a new mouse model. The infection of non-congenic ICR mouse strain with lethal P. yoelii leads to three malaria clinical evolution. The worst prognosis is associated with the increase in the circulation of innate immune cells, CD4+CD25+ cells and immature B cells and is accompanied by overproduction of cytokines in the most critical time point of the infection. Surviving mice are characterized by the increase in circulating activated T cells and B cells at the end of the infection. In surviving mice, a single infection is able to generate memory B cells that are maintained for more than a year in spleen. Finally, mice which survive, after chemotherapy or spontaneously, to the infection after showing a parasitemia, develop a long-term protective humoral response against reinfections. The absence of parasite exposure between reinfections decreases both the antibody avidity for it antigen and the repertoire of Plasmodium antigens recognized by the antibodies.
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Veterinaria, Departamento de Bioquímica y Biología Molecular IV, leída el 05-07-2013. Tesis formato europeo (compendio de artículos).