Abstract
Individuals that are exposed to malaria eventually develop immunity to the disease with one possible mechanism being the gradual acquisition of antibodies to the range of parasite variant surface antigens in their local area. Major antibody targets include the large and highly polymorphic Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family of proteins. Here, we use a protein microarray containing 123 recombinant PfEMP1-DBLα domains (VAR) from Papua New Guinea to seroprofile 38 nonimmune children (<4 years) and 29 hyperimmune adults (≥15 years) from the same local area. The overall magnitude, prevalence and breadth of antibody response to VAR was limited at <2 years and 2–2.9 years, peaked at 3–4 years and decreased for adults compared with the oldest children. An increasing proportion of individuals recognized large numbers of VAR proteins (>20) with age, consistent with the breadth of response stabilizing with age. In addition, the antibody response was limited in uninfected children compared with infected children but was similar in adults irrespective of infection status. Analysis of the variant-specific response confirmed that the antibody signature expands with age and infection. This also revealed that the antibody signatures of the youngest children overlapped substantially, suggesting that they are exposed to the same subset of PfEMP1 variants. VAR proteins were either seroprevalent from early in life, (<3 years), from later in childhood (≥3 years) or rarely recognized. Group 2 VAR proteins (Cys2/MFK-REY+) were serodominant in infants (<1-year-old) and all other sequence subgroups became more seroprevalent with age. The results confirm that the anti-PfEMP1-DBLα antibody responses increase in magnitude and prevalence with age and further demonstrate that they increase in stability and complexity. The protein microarray approach provides a unique platform to rapidly profile variant-specific antibodies to malaria and suggests novel insights into the acquisition of immunity to malaria.
Highlights
Individuals that are exposed to malaria eventually develop immunity to the disease with one possible mechanism being the gradual acquisition of antibodies to the range of parasite variant surface antigens in their local area
We describe the analysis of antibodies to Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) in Papua New Guinean (PNG) children and adults who are exposed to malaria, using a protein microarray fabricated with 123 recombinant PfEMP1-Duffy Binding Like (DBL)␣ domains sampled from parasites infecting the same human population [20]
Profiling the Anti-PfEMP1 Antibody Repertoire with Protein Microarrays—Protein microarrays fabricated with 128 recombinant PfEMP1-DBL␣ domains (VAR proteins) of which 123 were successfully expressed, were used to measure antibody reactivity in human plasma samples
Summary
Individuals that are exposed to malaria eventually develop immunity to the disease with one possible mechanism being the gradual acquisition of antibodies to the range of parasite variant surface antigens in their local area. Recent evidence shows that this hierarchy of var gene expression is imprinted in the host antibody response, with antibodies against recombinant PfEMP1 domains from the P. falciparum reference strain, 3D7, showing a marked bias toward group A var genes in very young children (Ͻ1-year-old) compared with broader recognition of all subgroups by older children and adults [36, 37]. Such PfEMP1 variants, if they could be isolated from natural parasite populations, may be ideal malaria vaccine candidates. The actual variants involved as well as the mechanisms underlying the acquisition of naturally acquired anti-PfEMP1 immunity are unclear
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