Experimental Cerebral Malaria is determined by initial Plasmodium host interaction

YUKO SATO; SABINE RIES; GEORGINA N. MONTAGNA; SIMON FILTRAEU; KAI MATUSCHEWSKI

Conferencia; 5th international conference on crossroads between innate and adaptive immunity, Aegean Conference; 2013

Malariais caused by blood infection with single cell eukaryotes of the genus Plasmodium. A fundamental question show the first encounter of parasite with the innate immune system shapes the development of protective and pathological immune responses. One severe clinical complication is cerebral malaria, leading to a high fatality rate and neurological damage. A murine model of experimental cerebral malaria (ECM)reproduces central aspects of this fatal outcome and permits comparative analysis of natural sporozoite-induced vs.transfusion-mediated infections.Several mouse mutants, such as myd88 and tlr2/4 mice, are refractory to ECM, indicative of central roles of the corresponding proteins in immunopathology. In this study, we wanted to develop a genetically modified parasite line that phenocopies ECM refractoriness in susceptible wild-type (WT) mice. We generated transgenic Plasmodium berghei parasites that display specific defects in sporozoite motility and identified one line that fails to induce ECM in C57BL/6 mice by sporozoite infection. These parasites infect and grow in mice with similar kinetics as WT sporozoites and retain full virulence, since transfusion-mediated infection resulted in ECM. This finding indicates that protection from ECM critically depends on the initial encounter after sporozoite transmission. Mice infected with transgenic sporozoites show an early up-regulation of systemic cytokines and an enhanced proliferation of distinct adaptive immune cells. Through comparative immune profiling of C57BL/6 mice infected with WT and transgenic sporozoites, our aim is to gain a better understanding of the innate immune mechanisms that predetermine whether a Plasmodium blood infection terminates inECM development or not.