Genesis of placental sequestration in malaria and possible targets for drugs for placental malaria

Abstract

Malaria during pregnancy results in intrauterine growth restriction, fetal anemia, and infant mortality. Women are more susceptible to malaria during pregnancy due to malaria-induced inflammation and the sequestration of infected red blood cells in the placenta, which bind to the chondroitin sulfate portion of syndecan-1 on the syncytiotrophoblast and in the intervillous space. Syndecan-1 is a dimeric proteoglycan with an extracellular ectodomain that is cleaved from the transmembrane domain (referred to as “shedding”) by matrix metalloproteinases (MMPs), likely the secreted MMP-9. The ectodomain includes four binding sites for chondroitin sulfate, which are proximal to the transmembrane domain, and six distal binding sites primarily for heparan sulfate. This “shedding” of syndecan-1 is inhibited by the presence of the heparan sulfate chains, which can be removed by heparanase. The intervillous space contains fibrin strands and syndecan-1 ectodomains free of heparan sulfate. The following is proposed as the sequence of events that leads to and is primarily responsible for sequestration in the intervillous space of the placenta. Inflammation associated with malaria triggers increased heparanase activity that degrades the heparan sulfate on the membrane-bound syndecan-1. Inflammation also upregulates MMP-9 and the removal of heparan sulfate gives MMP-9 access to cleave syndecan-1, thereby releasing dimeric syndecan-1 ectodomains with at least four chondroitin sulfate chains attached. These multivalent ectodomains bind infected RBCs together leading to their aggregation and entrapment in intervillous fibrin. This mechanism suggests possible new targets for anti-placental malaria drugs such as the inhibition of MMP-9. Doxycycline is an antimalarial drug which inhibits MMP-9.