Trends in Parasitology
Volume 26, Issue 8, August 2010, Pages 412-419
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Of mice and women: rodent models of placental malaria

https://doi.org/10.1016/j.pt.2010.04.010Get rights and content

Pregnant women are at increased malaria risk. The infections are characterized by placental accumulation of infected erythrocytes (IEs) with adverse consequences for mother and baby. Placental IE sequestration in the intervillous space is mediated by variant surface antigens (VSAs) selectively expressed in placental malaria (PM) and specific for chondroitin sulfate A (CSA). In Plasmodium falciparum, these VSAPM appear largely synonymous with the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family variant VAR2CSA. As rodent malaria parasites do not possess PfEMP1 homologs, the usefulness of experimental mouse PM models remains controversial. However, many features of murine and human PM are similar, including involvement of VSAs analogous to PfEMP1. It thus appears that rodent model studies can further the understanding of VSA-dependent malaria pathogenesis and immunity.

Section snippets

Placental malaria: Plasmodium falciparum and the extended family

Infection with Plasmodium falciparum parasites during pregnancy can have serious adverse consequences for the mother and not least her baby and is estimated to be the cause of up to 200 000 infant deaths per year [1]. The marked placental accumulation of infected erythrocytes (IEs), which is the central feature of malaria during pregnancy (Box 1), has been known for at least a century [2], but a detailed understanding of the pathogenesis of placental malaria (PM) and the role of immunity in

Malaria during pregnancy in non-immune rodents

P. berghei infections are uniformly fatal in non-immune pregnant and non-pregnant rodents, but the course of P. berghei infection is accelerated in pregnant mice 12, 13, whereas it appears to be more variable in rats 14, 15. Early infection of pregnant mice generally causes abortion, though pregnancy often proceeds after later infection, yet with clear signs of pathology in the mother as well as the offspring 9, 12, 16. Complications include foetal resorption, intrauterine growth retardation,

Malaria in immune, pregnant mice

In 1980, van Zon et al. published a study [30] which differed from all its predecessors in its focus on mice that had been rendered immune to P. berghei infection prior to mating. Clearly, this approach much better simulates the situation facing primigravidae in areas of intense parasite transmission, and the authors proposed their model as a convenient tool to study why previously acquired protective immunity to P. falciparum infection fails during pregnancy. They found that if virgin mice

Placental malaria in humans

Whereas non-immune animals dominate studies of malaria in pregnant rodents, there are only a few studies of P. falciparum infection during pregnancy in women with limited or no pre-existing anti-malarial immunity [36]. Overall, studies from low-endemicity settings report that infections are symptomatic with substantial peripheral parasitaemia and that pregnant women are at increased risk of malaria compared to men and non-pregnant women. If untreated, such infections often progress to severe

Human reality and murine simulations of it

Today, there is ample evidence that VSAs are both important determinants of the pathogenesis of P. falciparum infection and major targets of naturally acquired protective immunity to malaria in general, and PM in particular 46, 58. However, the important studies by van Zon et al. on P. berghei pre-immunized pregnant mice 34, 35 were conducted at a time when the importance of VSA-specific immunity in malaria was not generally appreciated, let alone its relevance to PM. Nevertheless, clinically

Concluding remarks, and the way forward

That pregnant women are at increased risk of malaria has been known for more than a century, and malaria in pregnant rodents has been studied for at least fifty years. Nevertheless, the relevance of mouse models to understanding the pathogenesis of, and immune response to, P. falciparum malaria is a continuing point of contention [69]. Such scepticism seems particularly justified where important antigens are absent from model parasites, as is the case for PfEMP1 in general and VAR2CSA in

Disclosure statement

We declare to have no actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations within three (3) years of beginning the work submitted that could inappropriately influence (bias) the contents of the present manuscript.

Acknowledgements

The financial support for our research from BioMalPar/EviMalaR, the Danish Medical Research Council, the Fundação para a Ciência e Tecnologia, Programa POCI 2010 and FEDER, and Rigshospitalet is gratefully acknowledged. John Steinbeck (and Mestas and Hughes) and Raymond Carver (and Haruki Murakami) are acknowledged for inspiring the title of this paper and the heading of Box 1, respectively.

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