VAR2CSA-Mediated Host Defense Evasion of Plasmodium falciparum Infected Erythrocytes in Placental Malaria

Abstract

Over 30 million women living in P. falciparum endemic areas are at risk of developing malaria during pregnancy every year. Placental malaria is characterized by massive accumulation of infected erythrocytes in the intervillous space of the placenta, accompanied by infiltration of immune cells, particularly monocytes. The consequent local inflammation and the obstruction of the maternofetal exchanges can lead to severe clinical outcomes for both mother and child. Even if protection against the disease can gradually be acquired following successive pregnancies, the malaria parasite has developed a large panel of evasion mechanisms to escape from host defense mechanisms and manipulate the immune system to its advantage. Infected erythrocytes isolated from placentas of women suffering from placental malaria present a unique phenotype and express the pregnancy-specific variant VAR2CSA of the Plasmodium falciparum Erythrocyte Membrane Protein (PfEMP1) family at their surface. The polymorphic VAR2CSA protein is able to mediate the interaction of infected erythrocytes with a variety of host cells including placental syncytiotrophoblasts and leukocytes but also with components of the immune system such as non-specific IgM. This review summarizes the described VAR2CSA-mediated host defense evasion mechanisms employed by the parasite during placental malaria to ensure its survival and persistence.

Keywords: PfEMP1; Plasmodium falciparum; VAR2CSA; VAR2CSA polymorphism; immune evasion; immuno-modulation; placental malaria.

Figure 1

Infected erythrocyte sequestration within the intervillous space of the placenta. (A) Schematic representation of infected erythrocytes (IE) adhering to the syncytiotrophoblastic lining of the fetal villus, with increased presence of macrophages and monocytes in the maternal blood. Parasite pigments (hemozoin) remain visible in macrophages following IEs phagocytosis. The natural transfer of gases and nutrients between maternal blood in the intervillous space and fetal blood circulating in the villi is impaired by IEs sequestration. E, Erythrocyte; ST, syncytiotrophoblast. (B) Architecture of the VAR2CSA protein and chemical structure of chondroitin-4-sulfate A. The circled region within VAR2CSA (ID1-ID2a) represents the CSA-binding region. The art pieces used in this figure were modified from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com/).

Figure 2

Evasion of antibody recognition and modulation of the placental environment by VAR2CSA-expressing infected erythrocytes. IgM binding to VAR2CSA could mask protein epitopes recognized by anti-VAR2CSA IgGs and consequently alter opsonic phagocytosis of IEs. PfEMP1 clustering on knob structures may act as an immune evasion mechanism, impairing antibody accessibility to key residues involved in CSA-binding. Due to extensive polymorphism, epitopes involved in each VAR2CSA functional process may differ among parasite strains. Furthermore, multiplicity of var2csa genes within the parasite genome may also confer a greater capacity for antigenic variation and evasion of variant-specific immune responses. The presence of VAR2CSA on the IEs surface could lead to decreased production of IL-1β, IL-6, IL-10, MCP-1, MIP-1α, and MIP-1β by monocytes and macrophages. VAR2CSA-dependent binding of IEs to syncytiotrophoblasts is able to activate MAPK pathways and lead to increased secretion of IL-8, IL-6, and soluble ICAM-1. The art pieces used in this figure were modified from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com/). The illustration of the protein sequence alignment is licensed under a Creative Commons Attribution, CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0/).