Molecular Principles of Intrauterine Growth Restriction in Plasmodium Falciparum Infection

Abstract

Malaria in pregnancy still constitutes a particular medical challenge in tropical and subtropical regions. Of the five Plasmodium species that are pathogenic to humans, infection with Plasmodium falciparum leads to fulminant progression of the disease with massive impact on pregnancy. Severe anemia of the mother, miscarriage, stillbirth, preterm delivery and intrauterine growth restriction (IUGR) with reduced birth weight are frequent complications that lead to more than 10,000 maternal and 200,000 perinatal deaths annually in sub-Saharan Africa alone. P. falciparum can adhere to the placenta via the expression of the surface antigen VAR2CSA, which leads to sequestration of infected erythrocytes in the intervillous space. This process induces a placental inflammation with involvement of immune cells and humoral factors. Especially, monocytes get activated and change the release of soluble mediators, including a variety of cytokines. This proinflammatory environment contributes to disorders of angiogenesis, blood flow, autophagy, and nutrient transport in the placenta and erythropoiesis. Collectively, they impair placental functions and, consequently, fetal growth. The discovery that women in endemic regions develop a certain immunity against VAR2CSA-expressing parasites with increasing number of pregnancies has redefined the understanding of malaria in pregnancy and offers strategies for the development of vaccines. The following review gives an overview of molecular processes in P. falciparum infection in pregnancy which may be involved in the development of IUGR.

Keywords: anemia; intrauterine growth restriction; malaria; placenta; plasmodium; pregnancy; small for gestational age.

Figure 1

Pathogenetic processes potentially contributing to the development of IUGR in placental malaria. The sequestration of infected erythrocytes expressing VAR2CSA in the intervillous space occurs through the binding to placental chondroitin sulfate (CSA). This process leads to the activation of syncytiotrophoblast cells and local monocytes. These cells secrete chemokines and cytokines, which attract further immune cells which contribute to the pathogenesis of fetal growth restriction. 1. Cell debris and fibrin deposits can disrupt placental blood flow and lead to hypoxia. 2. Elevated EV may carry modified patterns of miRNAs disturbing trophoblast functions. 3–4. Activated complement factors (C5a) and inflammatory responses alter the concentration of cytokines, angiogenic and growth factors, affecting vascularization and placental growth. Cytokines and decreased growth factors impact placental nutrient transporters, resulting in decreased amino acid and glucose transport. 5. The suppressed erythropoiesis is caused either directly via cytokines or indirectly via increased hepatic hepcidin and lowered iron levels. 6. Dyserythropoiesis is a consequence of hemozoin deposits in the bone marrow, which disturb blood formation directly via apoptosis induction or indirectly via inflammatory mediators such as nitric oxide (NO). 7. Phagocytosis and hemolysis reduce erythrocyte numbers contributing to anemia. Together with placental alterations, maternal anemia leads to fetal growth restriction. , disturbed; ↑, increased; ↓, decreased; AA, amino acids; C5a, activated complement factor 5; CSA, chondroitin sulfate A, EV, extracellular vesicles; IL, interleukin; NO, nitric oxide; TNF, tumor necrosis factor.

Figure 2

Simplified illustration of the interaction between VAR2CSA and CSA in the placenta. (A) P. falciparum expresses VAR2CSA on the surface of infected erythrocytes, which in turn binds to CSA in the intervillous space. Pf, P. falciparum within a parasitophorous vacuole; CSA, chondroitin sulfate A. (B) Enlarged view of (A). VAR2CSA binds to CSA with its N-terminal domains. ATS, Acidic terminal segment; DBL, Duffy-binding-like domain; ID, Interdomain; NTS, N-terminal segment.