Prognostic Indicators of Life-Threatening Malaria Are Associated with Distinct Parasite Variant Antigen Profiles

Two key clinical indicators of life-threatening malaria in African children may be associated with differential expression of parasite surface antigens on infected erythrocytes. Malaria: A Parasite’s Perspective Malaria is still a major cause of childhood deaths worldwide. However, the reasons why some children get life-threatening disease and others only suffer mild symptoms are still poorly understood. Part of the problem is the considerable variation both in the molecular characteristics of the parasites that cause the disease and in the manifestations of the disease itself. A new study by Bull, Warimwe, and colleagues explores a family of variable parasite molecules (PfEMP1), whose main function appears to be direct interaction with the human host. These molecules have two important features. First, different PfEMP1 variants have different binding properties, meaning that they can bind to different host molecules. Second, each individual parasite has the genetic information to make about 60 different versions of PfEMP1; switching between versions is programmed by the parasite. This means that the physical interaction between the parasite and its human host can vary, potentially explaining the variation in clinical manifestations among clinical cases. The study focuses on two major manifestations of life-threatening malaria in hospitalized African children: respiratory distress and impaired consciousness. The authors studied malaria parasites sampled from children with these manifestations and found that the properties of these parasites differed from each other and from parasites obtained from children without these clinical manifestations. Children with respiratory distress tended to be infected with parasites that bound to uninfected erythrocytes (a phenotype called “rosetting”), whereas parasites from children with impaired consciousness frequently expressed high levels of a subset of PfEMP1 variants called “group A–like” PfEMP1 without exhibiting high rosetting. Knowledge that different manifestations of malaria may be associated with distinct types of the host-parasite interaction will help to focus efforts to standardize the phenotyping of the disease and may help in the development of specific interventions in the future. PfEMP1 is a family of cytoadhesive surface antigens expressed on erythrocytes infected with Plasmodium falciparum, the parasite that causes the most severe form of malaria. These surface antigens play a role in immune evasion and are thought to contribute to the pathogenesis of the malaria parasite. Previous studies have suggested a role for a specific subset of PfEMP1 called “group A” in severe malaria. To explore the role of group A PfEMP1 in disease, we measured the expression of the var genes that encode them in parasites from clinical isolates collected from children suffering from malaria. We also looked at the ability of these clinical isolates to induce rosetting of erythrocytes, which indicates a cytoadhesion phenotype that is thought to be important in pathogenesis. These two sets of data were correlated with the presence of two life-threatening manifestations of severe malaria in the children: impaired consciousness and respiratory distress. Using regression analysis, we show that marked rosetting was associated with respiratory distress, whereas elevated expression of group A–like var genes without elevated rosetting was associated with impaired consciousness. The results suggest that manifestations of malarial disease may reflect the distribution of cytoadhesion phenotypes expressed by the infecting parasite population.