Adhesion of Plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria

Abstract

Infection with Plasmodium falciparum during pregnancy leads to the accumulation of parasite-infected erythrocytes in the placenta, and is associated with excess perinatal mortality, premature delivery and intrauterine growth retardation in the infant, as well as increased maternal mortality and morbidity. P. falciparum can adhere to specific receptors on host cells, an important virulence factor enabling parasites to accumulate in various organs. We report here that most P. falciparum isolates from infected placentae can bind to hyaluronic acid, a newly discovered receptor for parasite adhesion that is present on the placental lining. In laboratory isolates selected for specific high-level adhesion, binding to hyaluronic acid could be inhibited by dodecamer or larger oligosaccharide fragments or polysaccharides, treatment of immobilized receptor with hyaluronidase, or treatment of infected erythrocytes with trypsin. In vitro flow-based assays demonstrated that high levels of adhesion occurred at low wall shear stress, conditions thought to prevail in the placenta. Our findings indicate that adhesion to hyaluronic acid is involved in mediating placental parasite accumulation, thus changing the present understanding of the mechanisms of placental infection, with implications for the development of therapeutic and preventative interventions.

Chondroitin Sulfate Proteoglycan but Not Hyaluronic Acid Is the Receptor for the Adherence of Plasmodium falciparum-Infected Erythrocytes in Human Placenta, and Infected Red Blood Cell Adherence Up-Regulates the Receptor Expression

“…In previous studies that reported IRBC binding to HA, bvhHA was used for the analysis of IRBC binding. [27][28][29][30] Therefore, we also assessed the coating of bvhHA to plastic plates. As shown in Figure 1A, a low but significant amount of HA was coated onto the plastic surface; the immobilization of HA when coated with bvhHA is likely through HABPs present in samples that are adsorbed onto the plastic surface.…”

“…[27][28][29][30] However, the presence of HA in human placenta at locations where IRBCs are known to adhere has not been demonstrated, and thus, it remains unclear whether HA is a receptor for placental IRBC adherence or not. If HA is indeed an additional receptor in the placenta for IRBC adherence, then this phenomenon has profound implications for the rational design of vaccine for women of child-bearing age, because a vaccine that specifically blocks the adherence of IRBC to C4S would not be sufficient to control placental infections.…”

Nonimmune immunoglobulin binding and multiple adhesion characterize Plasmodium falciparum -infected erythrocytes of placental origin

“…There are, however, reports pinpointing the possible role of other receptors in placental sequestration. Hyaluronic acid (HA), yet another GAG, has been reported to interact with placental isolates (15). Some isolates bind solely to HA, whereas others interact with both HA and CSA.…”

Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis ofPlasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-α Secretion by Monocytes/Macrophages

“…The central pathophysiologic events in severe Plasmodium falciparum malaria are the inability of the host defenses to control parasite replication, cytokine imbalance resulting in the excessive release of proinflammatory cytokines in response to infection, and the sequestration of parasitized erythrocytes (PEs) 3 in the microvasculature of vital organs (2)(3)(4)(5)(6). Several receptors have been implicated in the cytoadherence of PEs to vascular endothelium, including ICAM-1 (7)(8), VCAM-1 (9 -10), E-selectin (10), platelet/endothelial cell adhesion molecule-1/CD31 (11), chondroitin-4-sulfate (12), hyaluronic acid (13), thrombospondin (TSP) (14), ␣ v ␤ 3 (15), and CD36 (16 -20).…”