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Abstract
Circumsporozoite protein (CS) is a leading vaccine antigen for falciparum malaria, but is highly polymorphic in natural parasite populations. The factors driving this diversity are unclear, but non-random assortment of the T cell epitopes TH2 and TH3 has been observed in a Kenyan parasite population. The recent publication of the crystal structure of the variable C terminal region of the protein allows the assessment of the impact of diversity on protein structure and T cell epitope assortment. Using data from the Gambia (55 isolates) and Malawi (235 isolates), we evaluated the patterns of diversity within and between epitopes in these two distantly-separated populations. Only non-synonymous mutations were observed with the vast majority in both populations at similar frequencies suggesting strong selection on this region. A non-random pattern of T cell epitope assortment was seen in Malawi and in the Gambia, but structural analysis indicates no intramolecular spatial interactions. Using the information from these parasite populations, structural analysis reveals that polymorphic amino acids within TH2 and TH3 colocalize to one side of the protein, surround, but do not involve, the hydrophobic pocket in CS, and predominately involve charge switches. In addition, free energy analysis suggests residues forming and behind the novel pocket within CS are tightly constrained and well conserved in all alleles. In addition, free energy analysis shows polymorphic residues tend to be populated by energetically unfavorable amino acids. In combination, these findings suggest the diversity of T cell epitopes in CS may be primarily an evolutionary response to intermolecular interactions at the surface of the protein potentially counteracting antibody-mediated immune recognition or evolving host receptor diversity.
Highlights
The development of a successful malaria vaccine has the potential to significantly reduce the estimated one million deaths a year caused by falciparum malaria
We describe polymorphism in the P. falciparum gene pfcsp in two natural parasite populations and map predicted amino acid substitutions onto the recently elucidated crystal structure of the C terminal end of the circumsporozoite protein (CS) protein
Concerns have been raised about the impact of antigen diversity on the development of effective malaria vaccines
Summary
The development of a successful malaria vaccine has the potential to significantly reduce the estimated one million deaths a year caused by falciparum malaria. Cell mediated immunity is thought to be mediated in part by T cell epitopes in the C terminus of the protein, including the epitopes known as TH2 and TH3 [7,8,9] These two epitopes are highly polymorphic in natural parasite populations [1,5]. Good et al suggested that they were maintained by natural selection favoring immune evasion (allele-specific immunity) [10] This hypothesis was supported by the observation that the number of nonsynonymous nucleotide substitutions was higher than synonymous nucleotide substitutions in parasite populations [11,12]. Recent studies of the population structure of the gene encoding CS (pfcsp) suggest that geographically variable levels of diversity and geographic restriction of specific subgroups may have an impact on the efficacy of malaria vaccines in specific geographic regions [18]. Evaluations of the polymorphisms within and associations between T cell epitopes need to be conducted in varying geographic locations to determine whether previous findings in one or two parasite populations are generalizable
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