Cytoadhesion of Plasmodium falciparum-infected erythrocytes and the infected placenta: a two-way pathway

Malaria is undoubtedly the world's most devastating parasitic disease, affecting 300 to 500 million people every year. Some cases of Plasmodium falciparum infection progress to the deadly forms of the disease responsible for 1 to 3 million deaths annually. P. falciparum-infected erythrocytes adhere to host receptors in the deep microvasculature of several organs. The cytoadhesion of infected erythrocytes to placental syncytiotrophoblast receptors leads to pregnancy-associated malaria (PAM). This specific maternal-fetal syndrome causes maternal anemia, low birth weight and the death of 62,000 to 363,000 infants per year in sub-Saharan Africa, and thus has a poor outcome for both mother and fetus. However, PAM and non-PAM parasites have been shown to differ antigenically and genetically. After multiple pregnancies, women from different geographical areas develop adhesion-blocking antibodies that protect against placental parasitemia and clinical symptoms of PAM. The recent description of a new parasite ligand encoded by the var2CSA gene as the only gene up-regulated in PAM parasites renders the development of an anti-PAM vaccine more feasible. The search for a vaccine to prevent P. falciparum sequestration in the placenta by eliciting adhesion-blocking antibodies and a cellular immune response, and the development of new methods for evaluating such antibodies should be key priorities in mother-child health programs in areas of endemic malaria. This review summarizes the main molecular, immunological and physiopathological aspects of PAM, including findings related to new targets in the P. falciparum var gene family. Finally, we focus on a new methodology for mimicking cytoadhesion under blood flow conditions in human placental tissue.

Antigenic variation at the surface of infected erythrocytes in plasmodium falciparum

Os membros da família dos genes var de Plasmodium falciparum codificam para receptores que desempenham um papel importante na patogenicidade da malária. O mecanismo responsável pela seleçäo da expressäo dos diferentes membros da família dos genes var ("switching") tem sido estdado utilizando populações de parasitas clonados, selecionados por suas características adesivas. O parasita expressa um único gene var o estágio de trofozoíto do seu ciclo de vida. Análises dos sítios de expressäo, ativos ou inativos, dos genes var demonstraram que o controle da expressäo ocorre durante a transcriçäo e a ativaçäo destes genes ocorre "in situ". Observamos que näo há sobreposiçäo no repertório dos genes var para diferentes isolados de laboratório, sugerindo desta maneira a existência de mecanismos para a geraçäo de diversidade desta família gênica. Experimentos de "fluorescence in situ hybridization" (FISH) mostraram que as extremidades dos cromossomos de P. falciparum estäo fisicamente associados e que esta formaçäo é importante para a geraçäo da diversidade dos genes var.

Mechanisms of protective immunity against asexual blood stages of Plasmodium falciparum in the experimental host Saimiri

In the Saimiri monkey, an experimental host for human malaria, acquired protection against Plasmodium falciparum blood stages depends on the IgG antibody populations developed. In vivo protective anti-falciparum activity of IgG antibodies is correlated with the in vivo opsonizing activity promoting phagocytosis of parasited red bloood cells. In contrast, non protective antibodies inhibit this mechanism by competing at the target level. A similar phenomenon can be and human infection. Anti-cytoadherent and anti-rosette antibodies developed by Saimiri and humans prevent the development of physiopathological events like cerebral malaria which can also occur in this experimental host. Furthermore, transfer to protective human anti-falciparum IgG antibodies into infected Saimiri monkeys exerts an anti parasite activity as efficient as that observed when it is transfered into acute falciparum malaria patients, making the Saimiri an even more attractive host. Studies on the role of immunocompetent cells in the protective immune reponse are still in their infancy, however the existance of a restricted polymorphism of MHC II class molecules in the Saimiri confers additional theoretical and practical importance to this model