| Grant number: | 10/18571-6 |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| Start date: | April 01, 2011 |
| End date: | March 31, 2015 |
| Field of knowledge: | Biological Sciences - Parasitology - Protozoology of Parasites |
| Principal Investigator: | Fabio Trindade Maranhão Costa |
| Grantee: | Marcele Fontenelle Bastos |
| Host Institution: | Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil |
Abstract It is believed that sequestration of Plasmodium falciparum-infected erythrocytes (Pf-iEs) in the microvasculature of vital organs contributes to the pathogenesis of severe malaria syndromes such as, cerebral malaria (CM), severe respiratory distress, severe anemia and malariain pregnancy (MiP). Despite treatment with effective antimalarial drugs, high mortality is still observed in severe cases of the disease. Thus, the use of adjuvant therapies has been suggested. Accordingly, sulfated polysaccharides, such as heparin, have been shown to prevent P. falciparum cytoadherence to several host receptors, inhibit merozoite invasion and disruptrosettes. Heparin was used in the past as treatment for severe malaria, however its use was abandoned due to the occurrence of serious side effects such as bleeding. Moreover, many ofthese compounds are derived from mammals, which increase the risk of contamination by pathogens, such as prions. Although many compounds have been tested as adjunct therapy to different pathophysiological features of severe malaria, none of them showed clear evidence of patients' improvement in clinical trials. Therefore, in this study, we investigated the action of two sulfated compounds extracted from invertebrates in P. falciparum cytoadhesion and development. It has been shown that these compounds - chondroitin sulfate fucosylated (FucCS),extracted from the sea cucumber Ludwigothurea grisea, and the heparin analogue (heparansulfate), extracted from the bivalve mollusk Nodipecten nodosus - have anticoagulant andantithrombotic action, but on a smaller scale than the commercial heparin. They also have antiinflammatoryand antimetastatic effect. Here, we show that FucCS and mollusk heparan sulfate (HS) were effective in inhibiting P. falciparum cytoadhesion, under static and flow conditions tohuman lung endothelial cells (HLECs). They were also able to block parasite development by interfering with merozoite invasion, and to disrupt rosettes efficiently. In addition, FucCSinhibited Pf-iEs adhesion to placenta cryosections. Finally, removal of sulfated fucose branches on the FucCS molecule virtually abolished its inhibitory effect, indicting a central role played by these structures. Then, we suggest FucCS and mollusk HS as promising candidates for adjunct therapy in the treatment of severe malaria and in preventing disease worsening. Also, we open new avenues to understand the mechanisms of action of these compounds in malaria treatment. (AU) | |
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