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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

Amino Acid Distribution in TH2 and TH3.The distributions of amino acids in the TH2 (Panel A) and TH3 (Panel B) epitopes are shown. The reference 3d7 amino acid sequences are shown on the X axis. Above the amino acid is a column representing the frequency of amino acids seen in isolates from Malawi (left half of the column) and the Gambia (right half of the column). The relative frequency of each amino acid is similar between the two geographically-distant African populations.
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pone-0062427-g004: Amino Acid Distribution in TH2 and TH3.The distributions of amino acids in the TH2 (Panel A) and TH3 (Panel B) epitopes are shown. The reference 3d7 amino acid sequences are shown on the X axis. Above the amino acid is a column representing the frequency of amino acids seen in isolates from Malawi (left half of the column) and the Gambia (right half of the column). The relative frequency of each amino acid is similar between the two geographically-distant African populations.

Mentions: Patterns of amino acid polymorphisms within the epitopes were then assessed. The sequence logo of the amino acid sequence for both countries (Figure 1) suggests positional bias in the diversity of CS. There were no significant differences between the two populations, with the exception that position 295 is variable in the Gambia, but monomorphic among the Malawian isolates. Within the TH2 and TH3 epitopes, the distribution and frequency of amino acid type were evaluated (Figure 4) showing highly similar amino acid polymorphisms, with similar frequencies, between the populations. Interestingly, within Malawi, we found 118 (50.2%) variants having at least a TH2 or TH3 epitope within one amino acid of the 3D7 (RTS,S vaccine) epitopes, while 230 (97.9%) have a TH2 or TH3 epitope within two amino acids of 3D7 epitopes. Using the sequence logo, we identified ten sites within the TSP domain which are most highly mutable, namely positions 314, 317, 318, 321, 322, 324, 327, 352, 357, and 361 (information content ≤3). These polymorphic sites predominately involve positively or negatively charged residues. Interestingly, positions 314, 317, 318, 321 and 324 can be populated by either positive or negative residues, suggesting that any charge-charge interactions are poorly conserved.


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)

Amino Acid Distribution in TH2 and TH3.The distributions of amino acids in the TH2 (Panel A) and TH3 (Panel B) epitopes are shown. The reference 3d7 amino acid sequences are shown on the X axis. Above the amino acid is a column representing the frequency of amino acids seen in isolates from Malawi (left half of the column) and the Gambia (right half of the column). The relative frequency of each amino acid is similar between the two geographically-distant African populations.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0062427-g004: Amino Acid Distribution in TH2 and TH3.The distributions of amino acids in the TH2 (Panel A) and TH3 (Panel B) epitopes are shown. The reference 3d7 amino acid sequences are shown on the X axis. Above the amino acid is a column representing the frequency of amino acids seen in isolates from Malawi (left half of the column) and the Gambia (right half of the column). The relative frequency of each amino acid is similar between the two geographically-distant African populations.
Mentions: Patterns of amino acid polymorphisms within the epitopes were then assessed. The sequence logo of the amino acid sequence for both countries (Figure 1) suggests positional bias in the diversity of CS. There were no significant differences between the two populations, with the exception that position 295 is variable in the Gambia, but monomorphic among the Malawian isolates. Within the TH2 and TH3 epitopes, the distribution and frequency of amino acid type were evaluated (Figure 4) showing highly similar amino acid polymorphisms, with similar frequencies, between the populations. Interestingly, within Malawi, we found 118 (50.2%) variants having at least a TH2 or TH3 epitope within one amino acid of the 3D7 (RTS,S vaccine) epitopes, while 230 (97.9%) have a TH2 or TH3 epitope within two amino acids of 3D7 epitopes. Using the sequence logo, we identified ten sites within the TSP domain which are most highly mutable, namely positions 314, 317, 318, 321, 322, 324, 327, 352, 357, and 361 (information content ≤3). These polymorphic sites predominately involve positively or negatively charged residues. Interestingly, positions 314, 317, 318, 321 and 324 can be populated by either positive or negative residues, suggesting that any charge-charge interactions are poorly conserved.

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