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. K E Y W O R D Sfibrin, heparanase, malaria, metalloproteinase, placenta, sequestration, syndecan-1

Placental Malaria

“…Differing from the other species, P. falciparum parasites express the P. falciparum erythrocyte membrane protein 1 (PfEMP1) receptor on infected RBC membranes [ 11 ]. During pregnancy, infected RBCs express a variant PfEMP1 receptor called VAR2CSA receptor that has an active Duffy-binding-like γ domain, which enables adherence and sequestration of infected RBCs in the intervillous spaces of the placenta [ 13 , 14 ].…”

Safety of Artemisinin Derivatives in the First Trimester of Pregnancy: A Controversial Story

“…In pregnant women, the accumulation of infected erythrocytes in the placenta accounts for low birth weight, infant anaemia and stillbirth [ 16 ]. Sequestration of infected erythrocytes in the placenta is due to the expression, on the surface of infected red blood cells, of variant surface antigens (VAR2CSA) able to mediate the adherence to placental chondroitin sulfate A and to other placental receptors [ 17 , 18 ]. This sequestration leads to mononuclear cell recruitment, placental damage, inflammation, clogging and failure to clear parasites through normal immunity [ 19 ].…”

Teratogen update: Malaria in pregnancy and the use of antimalarial drugs in the first trimester

“…Other effects of malaria infection during pregnancy on the offspring include intrauterine growth restriction (small for gestational age), fetal and postnatal anemia, transplacental transmission of malaria/congenital malaria, preterm birth and peri‐ and postnatal mortality (Brabin, 1983; Brabin et al, 2004; Clark, 2019; Cottrell, Mary, Barro, & Cot, 2007; De Beaudrap et al, 2013; Desai et al, 2007; Dorman et al, 2002; Griffin et al, 2012; Malhotra et al, 2006; Menendez et al, 2000; Moore, Simpson, et al, 2017; Park et al, 2020; Thompson et al, 2020; Uneke, 2007a, 2007b).…”

“…Sequestration in the placenta requires a change in the PfEMP1 receptors on the surface of IRBCs. Parasites that produce PfEMP1 receptors with CIDR domains that bind to CD36 surface proteins can switch to producing PfEMP1 receptors that instead bind to the chondroitin sulfate arms of the proteoglycan syndecan‐1 on the surface of the syncytiotrophoblast and in the intervillous space (Clark, 2019; Pereira et al, 2016). These are referred to as VAR2CSA receptors.…”

“…In a study in Tanzania in which 34% of women had malaria, 19.4% of first‐time mothers (with and without malaria) had placental malaria (Muehlenbachs et al, 2010). Across 21 studies conducted in nine sub‐Saharan African countries in which evidence of malaria was not a criterion for enrollment (studies were reported between 1925 and 2017), the percentage of 10,032 term pregnancies that were infected with placental malaria was 29.9% (Brabin, 1983; Clark, 2019).…”