Sequence Diversity in the <italic toggle="yes">pe_pgrs</italic> Genes of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Independent of Human T Cell Recognition
ABSTRACT The Mycobacterium tuberculosis genome includes the large family of pe_pgrs genes, whose functions are unknown. Because of precedents in other pathogens in which gene families showing high sequence variation are involved in antigenic variation, a similar role has been proposed for the pe_pgr...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2014-02-01
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| Series: | mBio |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00960-13 |
| _version_ | 1818406377127673856 |
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| author | Richard Copin Mireia Coscollá Salome N. Seiffert Graham Bothamley Jayne Sutherland Georgetta Mbayo Sebastien Gagneux Joel D. Ernst |
| author_facet | Richard Copin Mireia Coscollá Salome N. Seiffert Graham Bothamley Jayne Sutherland Georgetta Mbayo Sebastien Gagneux Joel D. Ernst |
| author_sort | Richard Copin |
| collection | DOAJ |
| description | ABSTRACT The Mycobacterium tuberculosis genome includes the large family of pe_pgrs genes, whose functions are unknown. Because of precedents in other pathogens in which gene families showing high sequence variation are involved in antigenic variation, a similar role has been proposed for the pe_pgrs genes. However, the impact of immune selection on pe_pgrs genes has not been examined. Here, we sequenced 27 pe_pgrs genes in 94 clinical strains from five phylogenetic lineages of the M. tuberculosis complex (MTBC). We found that pe_pgrs genes were overall more diverse than the remainder of the MTBC genome, but individual members of the family varied widely in their nucleotide diversity and insertion/deletion (indel) content: some were more, and others were much less, diverse than the genome average. Individual pe_pgrs genes also differed in the ratio of nonsynonymous to synonymous mutations, suggesting that different selection pressures act on individual pe_pgrs genes. Using bioinformatic methods, we tested whether sequence diversity in pe_pgrs genes might be selected by human T cell recognition, the major mechanism of adaptive immunity to MTBC. We found that the large majority of predicted human T cell epitopes were confined to the conserved PE domain and experimentally confirmed the antigenicity of this domain in tuberculosis patients. In contrast, despite being genetically diverse, the PGRS domains harbored few predicted T cell epitopes. These results indicate that human T cell recognition is not a significant force driving sequence diversity in pe_pgrs genes, which is consistent with the previously reported conservation of human T cell epitopes in the MTBC. IMPORTANCE Recognition of Mycobacterium tuberculosis antigens by T lymphocytes is known to be important for immune protection against tuberculosis, but it is unclear whether human T cell recognition drives antigenic variation in M. tuberculosis. We previously discovered that the known human T cell epitopes in the M. tuberculosis complex are highly conserved, but we hypothesized that undiscovered epitopes with naturally occurring sequence variants might exist. To test this hypothesis, we examined the pe_pgrs genes, a large family of genes that has been proposed to function in immune evasion by M. tuberculosis. We found that the pe_pgrs genes exhibit considerable sequence variation, but the regions containing T cell epitopes and the regions of variation are distinct. These findings confirm that the majority of human T cell epitopes of M. tuberculosis are highly conserved and indicate that selection forces other than T cell recognition drive sequence variation in the pe_pgrs genes. |
| first_indexed | 2024-12-14T09:10:58Z |
| format | Article |
| id | doaj.art-da230445c41e4c80adce2e2ce91e60ee |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-14T09:10:58Z |
| publishDate | 2014-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-da230445c41e4c80adce2e2ce91e60ee2022-12-21T23:08:34ZengAmerican Society for MicrobiologymBio2150-75112014-02-015110.1128/mBio.00960-13Sequence Diversity in the <italic toggle="yes">pe_pgrs</italic> Genes of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Independent of Human T Cell RecognitionRichard Copin0Mireia Coscollá1Salome N. Seiffert2Graham Bothamley3Jayne Sutherland4Georgetta Mbayo5Sebastien Gagneux6Joel D. Ernst7Department of Medicine, Division of Infectious Diseases, New York University School of Medicine, New York, New York, USADepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, SwitzerlandDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, SwitzerlandHomerton University Hospital NHS Foundation Trust, London, United KingdomTB Immunology Laboratory, Vaccinology Theme, Medical Research Council Unit, Fajara, the GambiaTB Immunology Laboratory, Vaccinology Theme, Medical Research Council Unit, Fajara, the GambiaDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, SwitzerlandDepartment of Medicine, Division of Infectious Diseases, New York University School of Medicine, New York, New York, USAABSTRACT The Mycobacterium tuberculosis genome includes the large family of pe_pgrs genes, whose functions are unknown. Because of precedents in other pathogens in which gene families showing high sequence variation are involved in antigenic variation, a similar role has been proposed for the pe_pgrs genes. However, the impact of immune selection on pe_pgrs genes has not been examined. Here, we sequenced 27 pe_pgrs genes in 94 clinical strains from five phylogenetic lineages of the M. tuberculosis complex (MTBC). We found that pe_pgrs genes were overall more diverse than the remainder of the MTBC genome, but individual members of the family varied widely in their nucleotide diversity and insertion/deletion (indel) content: some were more, and others were much less, diverse than the genome average. Individual pe_pgrs genes also differed in the ratio of nonsynonymous to synonymous mutations, suggesting that different selection pressures act on individual pe_pgrs genes. Using bioinformatic methods, we tested whether sequence diversity in pe_pgrs genes might be selected by human T cell recognition, the major mechanism of adaptive immunity to MTBC. We found that the large majority of predicted human T cell epitopes were confined to the conserved PE domain and experimentally confirmed the antigenicity of this domain in tuberculosis patients. In contrast, despite being genetically diverse, the PGRS domains harbored few predicted T cell epitopes. These results indicate that human T cell recognition is not a significant force driving sequence diversity in pe_pgrs genes, which is consistent with the previously reported conservation of human T cell epitopes in the MTBC. IMPORTANCE Recognition of Mycobacterium tuberculosis antigens by T lymphocytes is known to be important for immune protection against tuberculosis, but it is unclear whether human T cell recognition drives antigenic variation in M. tuberculosis. We previously discovered that the known human T cell epitopes in the M. tuberculosis complex are highly conserved, but we hypothesized that undiscovered epitopes with naturally occurring sequence variants might exist. To test this hypothesis, we examined the pe_pgrs genes, a large family of genes that has been proposed to function in immune evasion by M. tuberculosis. We found that the pe_pgrs genes exhibit considerable sequence variation, but the regions containing T cell epitopes and the regions of variation are distinct. These findings confirm that the majority of human T cell epitopes of M. tuberculosis are highly conserved and indicate that selection forces other than T cell recognition drive sequence variation in the pe_pgrs genes.https://journals.asm.org/doi/10.1128/mBio.00960-13 |
| spellingShingle | Richard Copin Mireia Coscollá Salome N. Seiffert Graham Bothamley Jayne Sutherland Georgetta Mbayo Sebastien Gagneux Joel D. Ernst Sequence Diversity in the <italic toggle="yes">pe_pgrs</italic> Genes of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Independent of Human T Cell Recognition mBio |
| title | Sequence Diversity in the <italic toggle="yes">pe_pgrs</italic> Genes of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Independent of Human T Cell Recognition |
| title_full | Sequence Diversity in the <italic toggle="yes">pe_pgrs</italic> Genes of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Independent of Human T Cell Recognition |
| title_fullStr | Sequence Diversity in the <italic toggle="yes">pe_pgrs</italic> Genes of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Independent of Human T Cell Recognition |
| title_full_unstemmed | Sequence Diversity in the <italic toggle="yes">pe_pgrs</italic> Genes of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Independent of Human T Cell Recognition |
| title_short | Sequence Diversity in the <italic toggle="yes">pe_pgrs</italic> Genes of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Independent of Human T Cell Recognition |
| title_sort | sequence diversity in the italic toggle yes pe pgrs italic genes of named content content type genus species mycobacterium tuberculosis named content is independent of human t cell recognition |
| url | https://journals.asm.org/doi/10.1128/mBio.00960-13 |
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