title: Fucosylated chondroitin sulfate inhibits Plasmodium falciparum cytoadhesion and merozoite invasion.
abstract: Sequestration of Plasmodium falciparum-infected erythrocytes (Pf-iEs) in the microvasculature of vital organs plays a key role in the pathogenesis of life-threatening malaria complications, such as cerebral malaria and malaria in pregnancy. This phenomenon is marked by the cytoadhesion of Pf-iEs to host receptors on the surfaces of endothelial cells, on noninfected erythrocytes, and in the placental trophoblast; therefore, these sites are potential targets for antiadhesion therapies. In this context, glycosaminoglycans (GAGs), including heparin, have shown the ability to inhibit Pf-iE cytoadherence and growth. Nevertheless, the use of heparin was discontinued due to serious side effects, such as bleeding. Other GAG-based therapies were hampered due to the potential risk of contamination with prions and viruses, as some GAGs are isolated from mammals. In this context, we investigated the effects and mechanism of action of fucosylated chondroitin sulfate (FucCS), a unique and highly sulfated GAG isolated from the sea cucumber, with respect to P. falciparum cytoadhesion and development. FucCS was effective in inhibiting the cytoadherence of Pf-iEs to human lung endothelial cells and placenta cryosections under static and flow conditions. Removal of the sulfated fucose branches of the FucCS structure virtually abolished the inhibitory effects of FucCS. Importantly, FucCS rapidly disrupted rosettes at high levels, and it was also able to block parasite development by interfering with merozoite invasion. Collectively, these findings highlight the potential of FucCS as a candidate for adjunct therapy against severe malaria.
authors.affiliation: Departamento de Genética, Evolução e Bioagentes, Universidade Estadual de Campinas, Campinas, Brazil.
authors.forename: Marcele F
authors.initials: MF
authors.lastname: Bastos
authors.forename: Letusa
authors.initials: L
authors.lastname: Albrecht
authors.forename: Eliene O
authors.initials: EO
authors.lastname: Kozlowski
authors.forename: Stefanie C P
authors.initials: SC
authors.lastname: Lopes
authors.forename: Yara C
authors.initials: YC
authors.lastname: Blanco
authors.forename: Bianca C
authors.initials: BC
authors.lastname: Carlos
authors.forename: Catarina
authors.initials: C
authors.lastname: Castiñeiras
authors.forename: Cristina P
authors.initials: CP
authors.lastname: Vicente
authors.forename: Claudio C
authors.initials: CC
authors.lastname: Werneck
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wunderlich
authors.forename: Marcelo U
authors.initials: MU
authors.lastname: Ferreira
authors.forename: Claudio R F
authors.initials: CR
authors.lastname: Marinho
authors.forename: Paulo A S
authors.initials: PA
authors.lastname: Mourão
authors.forename: Mauro S G
authors.initials: MS
authors.lastname: Pavão
authors.forename: Fabio T M
authors.initials: FT
authors.lastname: Costa
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000009:adverse effects / Q000494:pharmacology*; D002478:Cells, Cultured; D002809:Chondroitin Sulfates / Q000009:adverse effects / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D056945:Hep G2 Cells; D006801:Humans; D052940:Merozoites / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D012616:Sea Cucumbers / Q000737:chemistry
chemical_list: D000962:Antimalarials; C517150:fucosylated chondroitin sulfate; D002809:Chondroitin Sulfates