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

Abstract

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 adhesionblocking antibodies that protect against placental parasitemia and clinical symptoms of PAM. The recent description of a new parasite ligand encoded by the var2 CSA 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.

Identification of VAR2CSA Domain-Specific Inhibitory Antibodies of the Plasmodium falciparum Erythrocyte Membrane Protein 1 Using a Novel Flow Cytometry Assay

“…Primigravid women are more susceptible to higher-density placental infections, resulting in maternal anemia, low birth weight, or death of the fetus (4,5,6). However, over multiple pregnancies, women acquire blocking antibodies that bind the parasite-encoded VAR2CSA protein expressed on the surface of parasite-IE and are associated with better pregnancy outcomes (7,8,9,10).…”

Understanding How Plasmodium falciparum Binds to the Placenta and Produces Pathology Provides a Rationale for Pregnancy-Associated Malaria Vaccine Development

“…For example, Costa et al, [37] advocated that a PAM vaccine should contain elements to induce significant IFN-secretion by T cells. This approach may indeed induce a strong cell-mediated immune response.…”

“…Gamain et al, [36] demonstrated that differences in binding are due to structural alterations in PfEMP-1, resulting in adherence to either receptor. This dichotomous relationship is due to the highly diverse var multigene family which encodes PfEMP-1 [37]. Only one variant of PfEMP-1 is expressed on the infected erythrocyte surface at a particular time; hence the var genes are considered mutually exclusive [37].…”

“…This dichotomous relationship is due to the highly diverse var multigene family which encodes PfEMP-1 [37]. Only one variant of PfEMP-1 is expressed on the infected erythrocyte surface at a particular time; hence the var genes are considered mutually exclusive [37]. Therefore, the majority of placental isolates bind to CSA and those in nonpregnant women adhere to CD36.…”

“…These chains need to reach 9 kDa in size to maintain parasite binding [37]. The CSA proteoglycan chains have an unusually low level of sulphate, with less than 10% of the disaccharide units being sulphated [48].…”