Pregnancy-associated malaria (PAM) or placental malaria is a presentation of the common illness that is particularly life-threatening to both mother and developing fetus. PAM is caused primarily by infection with Plasmodium falciparum, the most dangerous of the four species of malaria-causing parasites that infect humans. During pregnancy, a woman faces a much higher risk of contracting malaria and of associated complications. Prevention and treatment of malaria are essential components of prenatal care in areas where the parasite is endemic.
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While the average adult citizen of an endemic region possesses some immunity to the parasite, pregnancy causes complications that leave the woman and fetus extremely vulnerable. The parasite interferes with transmission of vital substances through the fetal placenta, often resulting in stillbirth, spontaneous abortion, or dangerously low birth weight. The tragedy of malaria in developing countries receives abundant attention from the international health community, but until recently PAM and its unique complications were not adequately addressed.
Signs and Symptoms
Women experiencing PAM may exhibit normal symptoms of malaria, but may also be asymptomatic or present with more mild symptoms, including a lack of the characteristic fever. This may prevent a woman from seeking treatment despite the danger to herself and her unborn child.
Cause
The disease results from the aggregation of erythrocytes infected by Plasmodium falciparum which have been shown to adhere to chondroitin sulfate A (CSA) on placental proteoglycans causing them to accumulate in the intervillous spaces of the placenta, blocking the crucial flow of nutrients from mother to embryo.
Epidemiology
Globally, an estimated 125 million or more pregnant women per year risk contracting PAM. Pregnancy-related malaria causes around 100,000 infant deaths each year, due in large part to low birth weight.
Mechanism
P. falciparum expresses proteins on the surface of parasite-infected erythrocytes (IE) helping them bind to an unusually low-sulfated form of chondroitin sulfate A (CSA) in the placental intervillous space. By this process, the parasite avoids being filtered through the spleen where it would be cleared from the bloodstream and killed. When selected in vitro for CSA-binding, the only upregulated gene expressed in the P. falciparum parasites was the var2csa gene. Parasite clones where the var2csa gene was disrupted lost the ability to adhere to CSA by blocking the binding of IE. Its protein, VAR2CSA (Variant Surface antigen 2-CSA), belongs to the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family and contains six Duffy binding-like (DBL) domains. The regions that mediate binding to CSA have not been defined, but DBL2, DBL3, and DBL6 have shown the highest affinity for CSA binding when testing with recombinant single-domains.
Current research
Each VAR2CSA domain has a potential affinity to CSA, but there are large areas not exposed to the immune system and appear to be buried in the quaternary structure. Data has indicated that these domains interact, forming a binding site that is specific for low-sulfated CSA found in the placenta. The binding of antibodies to one of these domains would prevent adhesion of parasitic IE in the placenta.
Moreover, studies have shown that women acquire immunity to PAM through antibody recognition of the VAR2CSA domain, also known as VSAPAM, after exposure during their first pregnancy. By measuring circulating levels of IgG antibodies that presumably target VAR2SCA, the study demonstrated that subsequent pregnancies confer progressively greater protection to PAM. Thus, PfEMP1 proteins such as the VAR2CSA domain could prove attractive as potential candidates for vaccine targets.