Quantitative Computer Image Analysis of Chondroitin Sulfate A Expression in Placentas Infected with Plasmodium Falciparum

Abstract

SUMMARYMost pathological conditions resulting from infection with the human malaria parasite Plasmodium falciparum occur as a consequence of the sequestration by several adhesion molecules of parasite-infected red blood cells (IRBCs). Recent reports have provided evidence that placental vascular endothelial ligands for IRBCs were mostly restricted to chondroitin sulfate A (CSA). The expression of CSA in malaria-infected placentas was investigated in a prospective case-control study in a hypoendemic area (Dakar, Senegal). The tissue distribution of CSA was measured in the terminal villi by immunostaining combined with image processing in 20 infected and 20 noninfected frozen sections of placenta. The villous surface immunostained by anti-CSA antibody was higher in infected than in noninfected placentas ( p Ͻ 0.03), in placentas with active infection than in those with past chronic infection ( p Ͻ 0.05), and in infected placentas with positive imprints than in those with negative imprints (not significant; p ϭ 0.06). Labeling was found in the extracellular matrix and in endothelial and stromal cells of all the placentas. Syncytiotrophoblast immunostaining was detected in all placentas associated with active or active chronic infection ( n ϭ 7) but in only 4/13 placentas with past chronic infection ( p Ͻ 0.01). The presence of P. falciparum in the imprint was significantly correlated with immunostaining of CSA in syncytiotrophoblasts ( p ϭ 0.003). These results suggest that CSA can play an important role in the sequestration of P. falciparum in human placentas during the acute phase of infection.

Characterization of VAR2CSA-deficient Plasmodium falciparum-infected erythrocytes selected for adhesion to the BeWo placental cell line

“…To evaluate whether CS2KO9 might represent a parasite type able to sequester in the placenta in a CSA-independent manner, adhesion of CS2 and CS2KO9 to ex vivo placental tissue sections was investigated [ 33 ]. CS2 IE bound to both the intervillous space and the placental syncytiotrophoblast and this binding was inhibited by free CSA and chondroitinase ABC treatment of tissue, consistent with the known distribution of CSA in placenta [ 8 ] (Figure 3a ). CS2KO9 bound at low levels to both IVS and SCT, and this binding was not inhibited by CSA or chondroitinase ABC (Figure 3a ).…”

“…The accumulation of Plasmodium falciparum -infected erythrocytes (IE) in the maternal placental intervillous space is thought to be mediated by interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of proteins expressed on the IE surface and placental receptors such as chondroitin sulfate A (CSA) and hyaluronic acid (HA) [ 6 , 7 ]. CSA is expressed by the placental syncytiotrophoblast layer, which lines the maternal blood spaces of the placenta [ 6 , 8 ]. PfEMP1 is also the dominant parasite derived variant surface antigen (VSA) expressed on IE, and immunity to placental malaria has been correlated with development of immunity to a PfEMP1 molecule, termed VAR2CSA (reviewed in [ 5 ]).…”

High Levels of Antibodies to Multiple Domains and Strains of VAR2CSA Correlate with the Absence of Placental Malaria in Cameroonian Women Living in an Area of High Plasmodium falciparum Transmission

“…In pregnant women, P. falciparum-infected erythrocytes (IE) bind to chondroitin sulfate A (CSA) (24,35), a glycosaminoglycan abundantly expressed in the intervillous space and on placental syncytiotrophoblast cells (1,2,40,48). Binding is mediated by VAR2CSA (variant surface antigen 2-chondroitin sulfate A), a variant antigen of the PfEMP1 family expressed on the surface of IE by the parasite (45,46).…”