Abstract
The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a variant surface antigen expressed on mature forms of infected erythrocytes. It is considered an important target of naturally acquired immunity. Despite its extreme sequence heterogeneity, variants of PfEMP1 can be stratified into distinct groups. Group A PfEMP1 have been independently associated with low host immunity and severe disease in several studies and are now of potential interest as vaccine candidates. Although antigen-specific antibodies are considered the main effector mechanism in immunity to malaria, the induction of efficient and long-lasting antibody responses requires CD4+ T-cell help. To date, very little is known about CD4+ T-cell responses to PfEMP1 expressed on clinical isolates. The DBLα-tag is a small region from the DBLα-domain of PfEMP1 that can be amplified with universal primers and is accessible in clinical parasite isolates. We identified the dominant expressed PfEMP1 in 41 individual clinical parasite isolates and expressed the corresponding DBLα-tag as recombinant antigen. Individual DBLα-tags were then used to activate CD4+ T-cells from acute and convalescent blood samples in children who were infected with the respective clinical parasite isolate. Here we show that CD4+ T-cell responses to the homologous DBLα-tag were induced in almost all children during acute malaria and maintained in some for 4 months. Children infected with parasites that dominantly expressed group A-like PfEMP1 were more likely to maintain antigen-specific IFNγ-producing CD4+ T-cells than children infected with parasites dominantly expressing other PfEMP1. These results suggest that group A-like PfEMP1 may induce long-lasting effector memory T-cells that might be able to provide rapid help to variant-specific B cells. Furthermore, a number of children induced CD4+ T-cell responses to heterologous DBLα-tags, suggesting that CD4+ T-cells may recognise shared epitopes between several DBLα-tags.
Highlights
Clinical immunity to malaria is achieved only after repeated infection with Plasmodium falciparum asexual bloodstage parasites
In children living in malaria- endemic areas, repeated exposure to a wide range of different Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on parasite isolates results in the acquisition of a repertoire of antibodies against different variants that is associated with protection [3,4]
Parasite isolates from children suffering from severe malaria or non-immune children were more likely to be recognised by sera from semi-immune children suggesting that parasites from non-immune children and those with severe disease express antigenically restricted repertoires of PfEMP1 [5,6]
Summary
Clinical immunity to malaria is achieved only after repeated infection with Plasmodium falciparum asexual bloodstage parasites. With the whole genome sequence of the laboratory isolate 3D7 it became evident that var genes encoding PfEMP1 can be grouped into three major types, Group A, B and C, suggesting their stratification into separate and potentially functionally distinct groups [7,8,9]. A schematic diagram of the DBLa-tag is shown in the Figure S1 Using this system we showed differential expression of distinct subgroups of var genes in parasite isolates from children suffering from different syndromes of severe disease and in non-immune children [11,13]. Whether serologically and genetically defined subgroups of PfEMP1 identify the same group of variants has not yet been determined
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