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MATERNAL MALARIA

What is maternal malaria?

Maternal or placental malaria is a common complication in regions where malaria is endemic, particularly among primigravidae, or women carrying their first pregnancy.  The mortality rate among pregnant women, in regions where malaria is unstab! le, is 2-10 times greater than it is among non-pregnant women.  In addition to death, maternal malaria is associated with premature delivery, intrauterine growth retardation (IUGR), perinatal mortality in the infant, and anemia and in the mother.!  These symptoms are in addition to traditional pathological outcomes of malaria.  Most reported cases of maternal malaria have been attributed to P.! falciparum.

 

How is the placenta targeted? 

Plasmodium falciparum malaria parasites in maternal placental sinus (B Gueft).

The placenta offers an advantageous location for the sequestration of infected red blood cells (iRBCs).  Parasite density in the placental tissue is not directly correlated to peripheral density.  Many inf! ected women present with zero peripheral parasitemia and significant placental load.  

Sequestration of iRBCs in the placenta relies on parasite adhesion to chondroitin sulfate A (CSA), a glycosaminoglycan receptor found throughout the extracellular matrix.  The putative ligand expressed by the parasite is PfCSA-L and it has been found to be antigenically conserved among global cases of maternal malaria. Furthermore, the differential expression of sp! ecific proteoglycans on the surface of endothelial cells ensures that only the CSA receptors on the placenta are accessible by P. falciparum.  

The parasites sequester along the surface of the placental membrane, specifically the trophoblastic villi, extravillous trophoblasts, and syncytial bridges. The sequestration of parasites impedes oxygen-nutrient transfer and can cause general hemor! rhaging. These pathological consequences contribute to the complications experienced by both mother and child.   

Recently, it has been proposed that the strain of P. falciparum implicated in maternal malaria is representative of a unique subpopulation.  It has been established, in vitro, that parasite isolates from inf! ected women do not bind to CD36, a nearly universal characteristic of P. falciparum.  CD36 is a surface molecule present on endothelial surfaces.                &n! bsp;        

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(a) Uninfected placental tissue.

(b) Binding of iRBCs to placental tissue

(Duffy and Fried, 1996)

 

  What is the immune response to maternal malaria?

The immune response to malaria is not well understood.  There has been some recent research into the unique IR offered by pregnant women against malaria.

One popular model, emerging in the last decade, to explain the unique susceptibility of pregnant women to malaria is that of pregnancy-associated immunosuppression.  According to this model, pregnancy induces a state of general immunosuppressi! on in the body sustained by elevated levels of serum cortisol.  This immunosuppression prevents fetal rejection and thus, renders pregnant women susceptible to infection.  However, this theory does not explain the diminished susceptibility t! o malaria experienced by multigravid women. 

It is well established that pregnant women display a bias towards type-2 cytokines.  Thus, they are rendered susceptible to many diseases requiring type 1 responses for protection.  These diseases include: TB, malaria, and leishmaniasis a! mong others.  However, in infected, pregnant women, IL-10 levels are decreased, while IFN-g , IL-2, and TNF-a levels are elevated--hal! lmarks of a type-1 cytokine response.  

These pro-inflammatory cytokines account for the pathology of maternal malaria.  Furthermore, elevated levels of TNF-a are associated with severe maternal anemia and consequently, signifi! cant pregnancy complications.  It is believed that anemia is caused by the suppression of placental erythropoietin.  Elevated levels of TNF-a are also associated with traditional sympto! mology of malaria.  In infected women, the cytokine elevation is localized, thus contributing to adverse pregnancy outcomes (Ramasamy).

 

  How do multigravids mount an effective immune response against malaria?

Most recently, it has been discovered that multigravid women can form strain-independent antibodies against CSA-specific parasites, and they demonstrate greatly diminished parasite load. Duffy and Fried have proposed that the unique susceptibility ! of primigravids to placental infection can be explained by their immune inexperience with the parasite subpopulation. Further, they have isolated in pregnant women purified IgG antibodies capable of blocking the parasite. This antibody response is not! associated with agglutination, which has been observed in vitro in infected CD36+ cell populations.

It is unclear whether/how cell mediated immunity contributes to this immune response.

 

  Is there hope for a vaccine?

Yes.  Although a general malaria vaccine appears to be a distant possibility, there is much hope for a vaccine against placental malaria. As aforementioned, Duffy and Fried have proven that multigravid women are able to mount an effective anti! body response against parasite sequestration on the placental surface. Presently, two possibilities have been explored with respect to parasite adhesion to the chondroitin sulfate A receptor. First, the administration of excessive soluble CSA to pregn! ant women has proven to drastically reduce parasite adhesion; however, in excess levels, this soluble protein is severely nephrotoxic. Second, studies have demonstrated that the administration of chondroitinase AC can effectively reduce parasite adhes! ion by 95%. This preliminary data is being further tested in combination with therapeutic use of monoclonal antibodies to CSA (Duffy and Fried).

 

 

 

Glycosaminoglycans are long, unbranched polysaccharide chains composed of repeating disaccharide units. This chain is linked to a core protein to form a proteoglycan molecule.