An unstable Th epitope of P. falciparum fosters central memory T cells and anti-CS antibody responses.
Malaria is transmitted by Plasmodium-infected anopheles mosquitoes. Widespread resistance of mosquitoes to insecticides and resistance of parasites to drugs highlight the urgent need for malaria vaccines. The most advanced malaria vaccines target sporozoites, the infective form of the parasite. A ma...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4077652?pdf=render |
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| author | Carlos A Parra-López David Bernal-Estévez Liusong Yin Luis Eduardo Vargas Carolina Pulido-Calixto Luz Mary Salazar J Mauricio Calvo-Calle Lawrence J Stern |
| author_facet | Carlos A Parra-López David Bernal-Estévez Liusong Yin Luis Eduardo Vargas Carolina Pulido-Calixto Luz Mary Salazar J Mauricio Calvo-Calle Lawrence J Stern |
| author_sort | Carlos A Parra-López |
| collection | DOAJ |
| description | Malaria is transmitted by Plasmodium-infected anopheles mosquitoes. Widespread resistance of mosquitoes to insecticides and resistance of parasites to drugs highlight the urgent need for malaria vaccines. The most advanced malaria vaccines target sporozoites, the infective form of the parasite. A major target of the antibody response to sporozoites are the repeat epitopes of the circumsporozoite (CS) protein, which span almost one half of the protein. Antibodies to these repeats can neutralize sporozoite infectivity. Generation of protective antibody responses to the CS protein (anti-CS Ab) requires help by CD4 T cells. A CD4 T cell epitope from the CS protein designated T* was previously identified by screening T cells from volunteers immunized with irradiated P. falciparum sporozoites. The T* sequence spans twenty amino acids that contains multiple T cell epitopes restricted by various HLA alleles. Subunit malaria vaccines including T* are highly immunogenic in rodents, non-human primates and humans. In this study we characterized a highly conserved HLA-DRβ1*04:01 (DR4) restricted T cell epitope (QNT-5) located at the C-terminus of T*. We found that a peptide containing QNT-5 was able to elicit long-term anti-CS Ab responses and prime CD4 T cells in HLA-DR4 transgenic mice despite forming relatively unstable MHC-peptide complexes highly susceptible to HLA-DM editing. We attempted to improve the immunogenicity of QNT-5 by replacing the P1 anchor position with an optimal tyrosine residue. The modified peptide QNT-Y formed stable MHC-peptide complexes highly resistant to HLA-DM editing. Contrary to expectations, a linear peptide containing QNT-Y elicited almost 10-fold lower long-term antibody and IFN-γ responses compared to the linear peptide containing the wild type QNT-5 sequence. Some possibilities regarding why QNT-5 is more effective than QNT-Y in inducing long-term T cell and anti-CS Ab when used as vaccine are discussed. |
| first_indexed | 2024-12-12T00:08:45Z |
| format | Article |
| id | doaj.art-e5ed228e943845fa86593a84728aa52e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T00:08:45Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-e5ed228e943845fa86593a84728aa52e2022-12-22T00:45:02ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0197e10063910.1371/journal.pone.0100639An unstable Th epitope of P. falciparum fosters central memory T cells and anti-CS antibody responses.Carlos A Parra-LópezDavid Bernal-EstévezLiusong YinLuis Eduardo VargasCarolina Pulido-CalixtoLuz Mary SalazarJ Mauricio Calvo-CalleLawrence J SternMalaria is transmitted by Plasmodium-infected anopheles mosquitoes. Widespread resistance of mosquitoes to insecticides and resistance of parasites to drugs highlight the urgent need for malaria vaccines. The most advanced malaria vaccines target sporozoites, the infective form of the parasite. A major target of the antibody response to sporozoites are the repeat epitopes of the circumsporozoite (CS) protein, which span almost one half of the protein. Antibodies to these repeats can neutralize sporozoite infectivity. Generation of protective antibody responses to the CS protein (anti-CS Ab) requires help by CD4 T cells. A CD4 T cell epitope from the CS protein designated T* was previously identified by screening T cells from volunteers immunized with irradiated P. falciparum sporozoites. The T* sequence spans twenty amino acids that contains multiple T cell epitopes restricted by various HLA alleles. Subunit malaria vaccines including T* are highly immunogenic in rodents, non-human primates and humans. In this study we characterized a highly conserved HLA-DRβ1*04:01 (DR4) restricted T cell epitope (QNT-5) located at the C-terminus of T*. We found that a peptide containing QNT-5 was able to elicit long-term anti-CS Ab responses and prime CD4 T cells in HLA-DR4 transgenic mice despite forming relatively unstable MHC-peptide complexes highly susceptible to HLA-DM editing. We attempted to improve the immunogenicity of QNT-5 by replacing the P1 anchor position with an optimal tyrosine residue. The modified peptide QNT-Y formed stable MHC-peptide complexes highly resistant to HLA-DM editing. Contrary to expectations, a linear peptide containing QNT-Y elicited almost 10-fold lower long-term antibody and IFN-γ responses compared to the linear peptide containing the wild type QNT-5 sequence. Some possibilities regarding why QNT-5 is more effective than QNT-Y in inducing long-term T cell and anti-CS Ab when used as vaccine are discussed.http://europepmc.org/articles/PMC4077652?pdf=render |
| spellingShingle | Carlos A Parra-López David Bernal-Estévez Liusong Yin Luis Eduardo Vargas Carolina Pulido-Calixto Luz Mary Salazar J Mauricio Calvo-Calle Lawrence J Stern An unstable Th epitope of P. falciparum fosters central memory T cells and anti-CS antibody responses. PLoS ONE |
| title | An unstable Th epitope of P. falciparum fosters central memory T cells and anti-CS antibody responses. |
| title_full | An unstable Th epitope of P. falciparum fosters central memory T cells and anti-CS antibody responses. |
| title_fullStr | An unstable Th epitope of P. falciparum fosters central memory T cells and anti-CS antibody responses. |
| title_full_unstemmed | An unstable Th epitope of P. falciparum fosters central memory T cells and anti-CS antibody responses. |
| title_short | An unstable Th epitope of P. falciparum fosters central memory T cells and anti-CS antibody responses. |
| title_sort | unstable th epitope of p falciparum fosters central memory t cells and anti cs antibody responses |
| url | http://europepmc.org/articles/PMC4077652?pdf=render |
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