Inmunidad a la malaria letal en modelos murinosadquisición espontánea o mediada por tratamiento quimioterapeútico

Abstract

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.