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

Aragam NR, Thayer KM, Nge N, Hoffman I, Martinson F, Kamwendo D, Lin FC, Sutherland C, Bailey JA, Juliano JJ - PLoS ONE (2013)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.

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.

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Related in: MedlinePlus

WebLogo of Amino Acid Sequence of Circumsporozoite Protein from Malawi and the Gambia.Panel A and Panel B are the Weblogos for Malawi and the Gambia, respectively. In Panel A, the TH2 region (blue) and TH3 region (pink) are underlined. The TH2 epitope maps almost exclusively to the α-helix, while the TH3 epitope maps to the flap. The polymorphic residues and types of amino acids that populate these sites appear to be conserved between two geographically disparate African parasite populations. Bits represent the information content, which is a relative measurement of sequence conservation, with higher values representing conservation and lower values consistent with sequence diversity at a position.
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pone-0062427-g001: WebLogo of Amino Acid Sequence of Circumsporozoite Protein from Malawi and the Gambia.Panel A and Panel B are the Weblogos for Malawi and the Gambia, respectively. In Panel A, the TH2 region (blue) and TH3 region (pink) are underlined. The TH2 epitope maps almost exclusively to the α-helix, while the TH3 epitope maps to the flap. The polymorphic residues and types of amino acids that populate these sites appear to be conserved between two geographically disparate African parasite populations. Bits represent the information content, which is a relative measurement of sequence conservation, with higher values representing conservation and lower values consistent with sequence diversity at a position.

Mentions: Sequences from Malawi (GenBank Accession numbers: JN634586– JN634642) were accessed from a previously published study from our group. Details of the sequencing from the 100 participants, which was done by massively parallel pyrosequencing on the 454 platform at University of North Carolina’s High Throughput Sequencing Facility, have previously been published [5]. This deep sequencing allowed for the detection and characterization of minor variants in an infection representing ≥1%. The Gambian pfcsp sequences (GenBank Accession numbers: JX885511–JX885521) derive from 55 participants in a clinical trial in the year 2000 [20], [21], and were generated by di-deoxy fluorescent capillary sequencing at The London School of Hygiene & Tropical Medicine (LSHTM). Both major and minor abundance sequence variants from each isolate are reported, where these were unambiguous, as previously described [20]. All sequences from both locales were trimmed to correspond to a 220 bp fragment containing nucleotides 871 to 1090 of PF3d7_0304600 (PlasmoDB, accessed 9/26/2012), corresponding to amino acids 291 to 363 (Figure 1). Consistent with the literature, TH2 was defined as amino acids 311–327 (PSDKHIKEYLNKIQNSL) and TH3 was defined as amino acids 352–363 (NKPKDELDYAND). Written informed consent as approved by The University of North Carolina, Malawian National Health Sciences Research Committee, the Medical Research Council/Gambian Government Joint Ethical Committee, and The London School of Hygiene & Tropical Medicine Ethics Committee was obtained from each participant.


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

Aragam NR, Thayer KM, Nge N, Hoffman I, Martinson F, Kamwendo D, Lin FC, Sutherland C, Bailey JA, Juliano JJ - PLoS ONE (2013)

WebLogo of Amino Acid Sequence of Circumsporozoite Protein from Malawi and the Gambia.Panel A and Panel B are the Weblogos for Malawi and the Gambia, respectively. In Panel A, the TH2 region (blue) and TH3 region (pink) are underlined. The TH2 epitope maps almost exclusively to the α-helix, while the TH3 epitope maps to the flap. The polymorphic residues and types of amino acids that populate these sites appear to be conserved between two geographically disparate African parasite populations. Bits represent the information content, which is a relative measurement of sequence conservation, with higher values representing conservation and lower values consistent with sequence diversity at a position.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646838&req=5

pone-0062427-g001: WebLogo of Amino Acid Sequence of Circumsporozoite Protein from Malawi and the Gambia.Panel A and Panel B are the Weblogos for Malawi and the Gambia, respectively. In Panel A, the TH2 region (blue) and TH3 region (pink) are underlined. The TH2 epitope maps almost exclusively to the α-helix, while the TH3 epitope maps to the flap. The polymorphic residues and types of amino acids that populate these sites appear to be conserved between two geographically disparate African parasite populations. Bits represent the information content, which is a relative measurement of sequence conservation, with higher values representing conservation and lower values consistent with sequence diversity at a position.
Mentions: Sequences from Malawi (GenBank Accession numbers: JN634586– JN634642) were accessed from a previously published study from our group. Details of the sequencing from the 100 participants, which was done by massively parallel pyrosequencing on the 454 platform at University of North Carolina’s High Throughput Sequencing Facility, have previously been published [5]. This deep sequencing allowed for the detection and characterization of minor variants in an infection representing ≥1%. The Gambian pfcsp sequences (GenBank Accession numbers: JX885511–JX885521) derive from 55 participants in a clinical trial in the year 2000 [20], [21], and were generated by di-deoxy fluorescent capillary sequencing at The London School of Hygiene & Tropical Medicine (LSHTM). Both major and minor abundance sequence variants from each isolate are reported, where these were unambiguous, as previously described [20]. All sequences from both locales were trimmed to correspond to a 220 bp fragment containing nucleotides 871 to 1090 of PF3d7_0304600 (PlasmoDB, accessed 9/26/2012), corresponding to amino acids 291 to 363 (Figure 1). Consistent with the literature, TH2 was defined as amino acids 311–327 (PSDKHIKEYLNKIQNSL) and TH3 was defined as amino acids 352–363 (NKPKDELDYAND). Written informed consent as approved by The University of North Carolina, Malawian National Health Sciences Research Committee, the Medical Research Council/Gambian Government Joint Ethical Committee, and The London School of Hygiene & Tropical Medicine Ethics Committee was obtained from each participant.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.

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.

Show MeSH
Related in: MedlinePlus