Plasmodium falciparum adhesion in the placenta

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Abstract

Plasmodium falciparum parasites sequester in the human placenta, and placental malaria is associated with disease and death of both mother and child. Placental isolates of P. falciparum uniformly bind to chondroitin sulfate A on the syncytiotrophoblast. Forms of the variant surface antigen PfEMP1 that bind chondroitin sulfate A in vitro (PfEMP1varCSA) are highly conserved in many field isolates. Two related forms of PfEMP1varCSA are commonly expressed by placental isolates, but these are also transcribed by most non-placental isolates. PfEMP1varCSA gene transcription is not upregulated when parasites are selected to bind chondroitin sulfate A, but other PfEMP1 forms may be upregulated. Young ring-stage parasites derived from chondroitin sulfate A-binding isolates may also bind to the endothelium through a process that does not involve PfEMP1 or chondroitin sulfate A. Adhesins and other surface proteins of placental parasites are targets of naturally occurring antibodies associated with protection and therefore could be used to develop vaccines that prevent malaria in pregnancy.

Introduction

Of the four malaria parasite species that infect humans, Plasmodium falciparum is the deadliest because it adheres to endothelium and sequesters within deep vascular beds of organs. During the red-cell stage of P. falciparum development, the intracellular parasite exports proteins to the red-cell surface, including adhesins that variously bind to host receptors such as CD36, intercellular adhesion molecule (ICAM)-1, and the glycosaminoglycan (GAG) chondroitin sulfate A (CSA). Adhesion allows the parasite to sequester in vascular beds where it avoids clearance in the spleen. The mass of sequestered parasites in the brain or the placenta can cause disease and death due to cerebral malaria and pregnancy malaria, respectively.

In areas of stable malaria transmission, adults enjoy immunity that limits parasitemia and prevents disease. Women become more susceptible during pregnancy, which was previously ascribed to pregnancy-related immunomodulation that develops to prevent rejection of the fetal allograft. However, susceptibility is greatest in primigravid women and diminishes over successive pregnancies, suggesting an acquired immune response to an antigenically distinct microbe. Placental isolates of P. falciparum commonly bind to CSA expressed on the surface of the syncytiotrophoblast (the cells lining the maternal vascular space in the placenta), and this phenotype is uncommon among isolates obtained from non-pregnant individuals [1]. The distinct binding phenotype renders pregnant women naı̈ve to this parasite population during their first pregnancy, after which, women residing in areas of stable malaria transmission develop antibodies that inhibit parasite adhesion to CSA [2]. These anti-adhesion antibodies are associated with a reduced mass of parasites in the placenta and substantial improvements in fetal development (PE Duffy and M Fried, unpublished data). Because CSA-binding parasites cross-react with sera donated by mothers throughout Asia and Africa, the antigen targeted by protective antibodies is presumed to have conserved features or limited diversity [2].

Section snippets

Adhesion receptors in the placenta

All studies so far have confirmed that placental isolates of P. falciparum adhere to CSA, but do not adhere or infrequently adhere to CD36 1., 3.. Because isolates donated by non-pregnant individuals are almost uniform in binding to CD36 (often in conjunction with adhesion to alternative receptors), the dichotomy in the distribution of the parasite phenotypes is striking [1].

Studies are also being carried out on other putative placental receptors (Figure 1). Hyaluronic acid (HA), a non-sulfated

Parasite adhesins that bind CSA

P. falciparum erythrocyte membrane protein 1 (PfEMP1) is a large, highly variant protein encoded by the family of var genes, of which each haploid genome is thought to have ∼60 copies. PfEMP1 is exported to the red-cell surface and has been implicated in immune evasion and adherence to several host receptors [10]. PfEMP1 has a two exon structure that encodes the highly variant extracellular and semiconserved intracytoplasmic elements, respectively. The extracellular region comprises domains

Adhesion of ring-stage parasites

Traditionally, only mature forms of P. falciparum were known to adhere and sequester. In Giemsa-stained smears of human peripheral blood samples, P. falciparum is distinguished from other malaria species by the exclusive appearance of young, ring-stage parasites, and the absence of mature trophozoites or schizonts (owing to their sequestration in deep vascular beds). Studies of CSA-binding parasites have modified this view, suggesting that a proportion of parasites that bind to CSA during their

Conclusions

P. falciparum adheres in the placenta via CSA and possibly other unusual receptors, and naturally acquired antibodies that block parasite adhesion to CSA are associated with protection from infection and disease. Forms of the variant antigen PfEMP1 that bind CSA in vitro are conserved in nature, but recent studies suggest that additional molecules might be involved in placental adhesion. Ring-stage parasites derived from CSA-binding lines may also adhere to the endothelium, but via a mechanism

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

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    of outstanding interest

Acknowledgements

We acknowledge support from National Institutes of Health (NIH) grants AI43680 and AI52059, and the Bill & Melinda Gates Foundation. The views expressed in this article are not necessarily those of the US Department of Defense.

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