Diversity of T cell epitopes in Plasmodium falciparum circumsporozoite protein likely due to protein-protein interactions
UMass Chan Affiliations
Department of Medicine, Division of Transfusion MedicineProgram in Bioinformatics and Integrative Biology
Document Type
ArticlePublication Date
2013-05-07Keywords
Amino Acid SequenceEpitopes, T-Lymphocyte
Models, Molecular
Molecular Sequence Data
Mutagenesis
Phylogeny
Plasmodium falciparum
Protein Binding
Protein Conformation
Protozoan ProteinsUMCCTS fundingImmunityImmunology of Infectious DiseaseParasitology
Metadata
Show full item recordAbstract
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.Source
Aragam NR, Thayer KM, Nge N, Hoffman I, Martinson F, et al. (2013) Diversity of T Cell Epitopes in Plasmodium falciparum Circumsporozoite Protein Likely Due to Protein-Protein Interactions. PLoS ONE 8(5): e62427. doi:10.1371/journal.pone.0062427. Link to article on publisher's siteDOI
10.1371/journal.pone.0062427Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30053PubMed ID
23667476Related Resources
Link to article in PubMedScopus Count
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