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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Autores principales:	Richard Copin, Mireia Coscollá, Salome N. Seiffert, Graham Bothamley, Jayne Sutherland, Georgetta Mbayo, Sebastien Gagneux, Joel D. Ernst
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/da230445c41e4c80adce2e2ce91e60ee
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spelling	oai:doaj.org-article:da230445c41e4c80adce2e2ce91e60ee2021-11-15T15:45:11ZSequence 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 Recognition10.1128/mBio.00960-132150-7511https://doaj.org/article/da230445c41e4c80adce2e2ce91e60ee2014-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00960-13https://doaj.org/toc/2150-7511ABSTRACT 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.Richard CopinMireia CoscolláSalome N. SeiffertGraham BothamleyJayne SutherlandGeorgetta MbayoSebastien GagneuxJoel D. ErnstAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 1 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 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
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.
format	article
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
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_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_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_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
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/da230445c41e4c80adce2e2ce91e60ee
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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

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