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

Abstract

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.

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

“…Studies to understand the role of PfEMP1 in SM pathogenesis have been mainly focused on children in Africa (15,18,19) and information on adult severe patients still remains scarce (43). However, in areas of unstable transmission, SM occurs across age groups.…”

“…Previously, logistic regression analysis was used to assign different binding variants to respiratory distress and impaired consciousness in pediatric malaria (46), but to our knowledge, this is the first time that more advanced machine-learning approaches have been used to understand parasite factors associated with disease progression and malaria severity. We expect that powerful machine-learning algorithms, such as those presented here, would be useful for analyzing var expression data from African children (15,18,19) and may shed light into pathogenesis mechanisms that drive pediatric cerebral malaria, respiratory distress, or anemia.…”

“…The extracellular domain of PfEMP1s presents a modular structure composed of adhesion domains, called Duffy bindinglike (DBL) and cysteine-rich interdomain region (CIDR) (12), which sometimes can be found in conserved tandem arrangements known as domain cassettes (DC) (13). Expression of group A PfEMP1 variants (14)(15)(16)(17)(18) and PfEMP1 encoding DC8 (15,19) have been strongly linked with pediatric severe malaria.…”

Evidence of strain structure in Plasmodium falciparum var gene repertoires in children from Gabon, West Africa

“…The obvious strain-structuring, immunedominant antigen in P. falciparum is PfEMP1 encoded by the var multigene family. PfEMP1 is also a virulence factor where expression of certain variants of PfEMP1 can lead to a variety of clinical outcomes in susceptible hosts (11)(12)(13)(14)(15). Even though var genes that encode PfEMP1 are prime candidates for disease surveillance to detect immune selection, they have not traditionally Significance This paper aims to discover how diverse malaria parasites are in children from an African village.…”

Mastering malaria: What helps and what hurts

“…PfEMP1 is encoded by the var multigene family, with ∼60 copies present in each parasite genome. The degree to which boosting plays a role in maintenance of immunity will depend on the extent of overlap between the PfEMP1 repertoires of different strains (11)(12)(13)) and its precise effects on incidence of different clinical syndromes will also be affected by their different propensities to cause severe disease (14)(15)(16). The dynamics of boosting of CD8 + T-cell responses against the liver stages will also differ in important ways from boosting of antibodies to sporozoite or merozoite antigens.…”