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    Diversity of T cell epitopes in Plasmodium falciparum circumsporozoite protein likely due to protein-protein interactions

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    Authors
    Aragam, Nagesh R.
    Thayer, Kelly M.
    Nge, Nabi
    Hoffman, Irving
    Martinson, Francis
    Kamwendo, Debbie
    Lin, Feng-Chang
    Sutherland, Colin
    Bailey, Jeffrey A.
    Juliano, Jonathan J.
    UMass Chan Affiliations
    Department of Medicine, Division of Transfusion Medicine
    Program in Bioinformatics and Integrative Biology
    Document Type
    Journal Article
    Publication Date
    2013-05-07
    Keywords
    Amino Acid Sequence
    Epitopes, T-Lymphocyte
    Models, Molecular
    Molecular Sequence Data
    Mutagenesis
    Phylogeny
    Plasmodium falciparum
    Protein Binding
    Protein Conformation
    Protozoan Proteins
    UMCCTS funding
    Immunity
    Immunology of Infectious Disease
    Parasitology
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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.
    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 site
    DOI
    10.1371/journal.pone.0062427
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/30053
    PubMed ID
    23667476
    Related Resources
    Link to article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pone.0062427
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    UMass Chan Faculty and Researcher Publications
    Program in Bioinformatics and Integrative Biology Publications
    UMass Center for Clinical and Translational Science Supported Publications

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