Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variation
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.18/4067 |
Resumo: | Insights into the genomic adaptive traits of Treponema pallidum, the causative bacterium of syphilis, have long been hampered due to the absence of in vitro culture models and the constraints associated with its propagation in rabbits. Here, we have bypassed the culture bottleneck by means of a targeted strategy never applied to uncultivable bacterial human pathogens to directly capture whole-genome T. pallidum data in the context of human infection. This strategy has unveiled a scenario of discreet T. pallidum interstrain single-nucleotide-polymorphism-based microevolution, contrasting with a rampant within-patient genetic heterogeneity mainly targeting multiple phase-variable loci and a major antigen-coding gene (tprK). TprK demonstrated remarkable variability and redundancy, intra- and interpatient, suggesting ongoing parallel adaptive diversification during human infection. Some bacterial functions (for example, flagella- and chemotaxis-associated) were systematically targeted by both inter- and intrastrain single nucleotide polymorphisms, as well as by ongoing within-patient phase variation events. Finally, patient-derived genomes possess mutations targeting a penicillin-binding protein coding gene (mrcA) that had never been reported, unveiling it as a candidate target to investigate the impact on the susceptibility to penicillin. Our findings decode the major genetic mechanisms by which T. pallidum promotes immune evasion and survival, and demonstrate the exceptional power of characterizing evolving pathogen subpopulations during human infection. |
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Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variationSyphilisTreponema pallidumWithin-patientGenetic VariationPhase VariationTrpKSexually Transmitted DiseasesInfectious DiseasesPublic HealthInfecções Sexualmente TransmissíveisInsights into the genomic adaptive traits of Treponema pallidum, the causative bacterium of syphilis, have long been hampered due to the absence of in vitro culture models and the constraints associated with its propagation in rabbits. Here, we have bypassed the culture bottleneck by means of a targeted strategy never applied to uncultivable bacterial human pathogens to directly capture whole-genome T. pallidum data in the context of human infection. This strategy has unveiled a scenario of discreet T. pallidum interstrain single-nucleotide-polymorphism-based microevolution, contrasting with a rampant within-patient genetic heterogeneity mainly targeting multiple phase-variable loci and a major antigen-coding gene (tprK). TprK demonstrated remarkable variability and redundancy, intra- and interpatient, suggesting ongoing parallel adaptive diversification during human infection. Some bacterial functions (for example, flagella- and chemotaxis-associated) were systematically targeted by both inter- and intrastrain single nucleotide polymorphisms, as well as by ongoing within-patient phase variation events. Finally, patient-derived genomes possess mutations targeting a penicillin-binding protein coding gene (mrcA) that had never been reported, unveiling it as a candidate target to investigate the impact on the susceptibility to penicillin. Our findings decode the major genetic mechanisms by which T. pallidum promotes immune evasion and survival, and demonstrate the exceptional power of characterizing evolving pathogen subpopulations during human infection.This study was partially supported by grant EXPL/BIA-MIC/0309/2013 from the Fundação para a Ciência e a Tecnologia (FCT).Repositório Científico do Instituto Nacional de SaúdePinto, MiguelBorges, VítorAntelo, MiniaPinheiro, MiguelNunes, AlexandraAzevedo, JacintaBorrego, Maria JoséMendonça, JoanaCarpinteiro, DinaVieira, LuísGomes, João Paulo.2016-10-28T10:19:21Z2016-10-172016-10-17T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/4067engNat Microbiol. 2016 Oct 17;2:16190. doi: 10.1038/nmicrobiol.2016.190.ESSN: 2058-527610.1038/nmicrobiol.2016.190.info:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:40:08Zoai:repositorio.insa.pt:10400.18/4067Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:38:54.209950Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variation |
title |
Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variation |
spellingShingle |
Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variation Pinto, Miguel Syphilis Treponema pallidum Within-patient Genetic Variation Phase Variation TrpK Sexually Transmitted Diseases Infectious Diseases Public Health Infecções Sexualmente Transmissíveis |
title_short |
Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variation |
title_full |
Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variation |
title_fullStr |
Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variation |
title_full_unstemmed |
Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variation |
title_sort |
Genome-scale analysis of the non-cultivable Treponema pallidum reveals extensive within-patient genetic variation |
author |
Pinto, Miguel |
author_facet |
Pinto, Miguel Borges, Vítor Antelo, Minia Pinheiro, Miguel Nunes, Alexandra Azevedo, Jacinta Borrego, Maria José Mendonça, Joana Carpinteiro, Dina Vieira, Luís Gomes, João Paulo. |
author_role |
author |
author2 |
Borges, Vítor Antelo, Minia Pinheiro, Miguel Nunes, Alexandra Azevedo, Jacinta Borrego, Maria José Mendonça, Joana Carpinteiro, Dina Vieira, Luís Gomes, João Paulo. |
author2_role |
author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
Pinto, Miguel Borges, Vítor Antelo, Minia Pinheiro, Miguel Nunes, Alexandra Azevedo, Jacinta Borrego, Maria José Mendonça, Joana Carpinteiro, Dina Vieira, Luís Gomes, João Paulo. |
dc.subject.por.fl_str_mv |
Syphilis Treponema pallidum Within-patient Genetic Variation Phase Variation TrpK Sexually Transmitted Diseases Infectious Diseases Public Health Infecções Sexualmente Transmissíveis |
topic |
Syphilis Treponema pallidum Within-patient Genetic Variation Phase Variation TrpK Sexually Transmitted Diseases Infectious Diseases Public Health Infecções Sexualmente Transmissíveis |
description |
Insights into the genomic adaptive traits of Treponema pallidum, the causative bacterium of syphilis, have long been hampered due to the absence of in vitro culture models and the constraints associated with its propagation in rabbits. Here, we have bypassed the culture bottleneck by means of a targeted strategy never applied to uncultivable bacterial human pathogens to directly capture whole-genome T. pallidum data in the context of human infection. This strategy has unveiled a scenario of discreet T. pallidum interstrain single-nucleotide-polymorphism-based microevolution, contrasting with a rampant within-patient genetic heterogeneity mainly targeting multiple phase-variable loci and a major antigen-coding gene (tprK). TprK demonstrated remarkable variability and redundancy, intra- and interpatient, suggesting ongoing parallel adaptive diversification during human infection. Some bacterial functions (for example, flagella- and chemotaxis-associated) were systematically targeted by both inter- and intrastrain single nucleotide polymorphisms, as well as by ongoing within-patient phase variation events. Finally, patient-derived genomes possess mutations targeting a penicillin-binding protein coding gene (mrcA) that had never been reported, unveiling it as a candidate target to investigate the impact on the susceptibility to penicillin. Our findings decode the major genetic mechanisms by which T. pallidum promotes immune evasion and survival, and demonstrate the exceptional power of characterizing evolving pathogen subpopulations during human infection. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-10-28T10:19:21Z 2016-10-17 2016-10-17T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.18/4067 |
url |
http://hdl.handle.net/10400.18/4067 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Nat Microbiol. 2016 Oct 17;2:16190. doi: 10.1038/nmicrobiol.2016.190. ESSN: 2058-5276 10.1038/nmicrobiol.2016.190. |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/embargoedAccess |
eu_rights_str_mv |
embargoedAccess |
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application/pdf |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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