Evolutionary Landscape of the <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Complex from the Viewpoint of PhoPR: Implications for Virulence Regulation and Application to Vaccine Development

ABSTRACT Different members of the Mycobacterium genus have evolved to cause tuberculosis in diverse human populations and in a variety of animal species. Our cumulative knowledge of mycobacterial genomes indicates that mutations in the PhoPR two-component virulence system were acquired not only duri...

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Autores principales:	Esther Broset, Carlos Martín, Jesús Gonzalo-Asensio
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/dc68ad2f42ef426fa0c0e7ef283f2033
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spelling	oai:doaj.org-article:dc68ad2f42ef426fa0c0e7ef283f20332021-11-15T15:41:31ZEvolutionary Landscape of the <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Complex from the Viewpoint of PhoPR: Implications for Virulence Regulation and Application to Vaccine Development10.1128/mBio.01289-152150-7511https://doaj.org/article/dc68ad2f42ef426fa0c0e7ef283f20332015-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01289-15https://doaj.org/toc/2150-7511ABSTRACT Different members of the Mycobacterium genus have evolved to cause tuberculosis in diverse human populations and in a variety of animal species. Our cumulative knowledge of mycobacterial genomes indicates that mutations in the PhoPR two-component virulence system were acquired not only during the natural evolution of mycobacterial species but also during in vitro subculture, which has given rise to the attenuated reference strain H37Ra or to different daughter strains of Mycobacterium bovis BCG. PhoPR is a well-known regulator of pathogenic phenotypes, including secretion of the virulence factor ESAT-6, biosynthesis of acyltrehalose-based lipids, and modulation of antigen export, in members of the Mycobacterium tuberculosis complex (MTBC). Evolutionarily conserved polymorphisms in PhoPR from Mycobacterium africanum, M. bovis, or M. tuberculosis H37Ra result in loss of functional phenotypes. Interestingly, some members of the MTBC have acquired compensatory mutations to counteract these polymorphisms and, probably, to maintain their pathogenic potential. Some of these compensatory mutations include the insertion of the IS6110 element upstream from phoPR in a particular M. bovis strain that is able to transmit between humans or polymorphisms in M. africanum and M. bovis that affect the regulatory region of the espACD operon, allowing PhoPR-independent ESAT-6 secretion. This review highlights the increasing knowledge of the significance of PhoPR in the evolution of the MTBC and its potential application in the construction of new attenuated vaccines based on phoPR inactivation. In this context, the live attenuated vaccine MTBVAC, based on a phoP fadD26 deletion mutant of M. tuberculosis, is the first vaccine of this kind to successfully enter into clinical development, representing a historic milestone in the field of human vaccinology.Esther BrosetCarlos MartínJesús Gonzalo-AsensioAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 5 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Esther Broset Carlos Martín Jesús Gonzalo-Asensio Evolutionary Landscape of the <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Complex from the Viewpoint of PhoPR: Implications for Virulence Regulation and Application to Vaccine Development
description	ABSTRACT Different members of the Mycobacterium genus have evolved to cause tuberculosis in diverse human populations and in a variety of animal species. Our cumulative knowledge of mycobacterial genomes indicates that mutations in the PhoPR two-component virulence system were acquired not only during the natural evolution of mycobacterial species but also during in vitro subculture, which has given rise to the attenuated reference strain H37Ra or to different daughter strains of Mycobacterium bovis BCG. PhoPR is a well-known regulator of pathogenic phenotypes, including secretion of the virulence factor ESAT-6, biosynthesis of acyltrehalose-based lipids, and modulation of antigen export, in members of the Mycobacterium tuberculosis complex (MTBC). Evolutionarily conserved polymorphisms in PhoPR from Mycobacterium africanum, M. bovis, or M. tuberculosis H37Ra result in loss of functional phenotypes. Interestingly, some members of the MTBC have acquired compensatory mutations to counteract these polymorphisms and, probably, to maintain their pathogenic potential. Some of these compensatory mutations include the insertion of the IS6110 element upstream from phoPR in a particular M. bovis strain that is able to transmit between humans or polymorphisms in M. africanum and M. bovis that affect the regulatory region of the espACD operon, allowing PhoPR-independent ESAT-6 secretion. This review highlights the increasing knowledge of the significance of PhoPR in the evolution of the MTBC and its potential application in the construction of new attenuated vaccines based on phoPR inactivation. In this context, the live attenuated vaccine MTBVAC, based on a phoP fadD26 deletion mutant of M. tuberculosis, is the first vaccine of this kind to successfully enter into clinical development, representing a historic milestone in the field of human vaccinology.
format	article
author	Esther Broset Carlos Martín Jesús Gonzalo-Asensio
author_facet	Esther Broset Carlos Martín Jesús Gonzalo-Asensio
author_sort	Esther Broset
title	Evolutionary Landscape of the <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Complex from the Viewpoint of PhoPR: Implications for Virulence Regulation and Application to Vaccine Development
title_short	Evolutionary Landscape of the <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Complex from the Viewpoint of PhoPR: Implications for Virulence Regulation and Application to Vaccine Development
title_full	Evolutionary Landscape of the <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Complex from the Viewpoint of PhoPR: Implications for Virulence Regulation and Application to Vaccine Development
title_fullStr	Evolutionary Landscape of the <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Complex from the Viewpoint of PhoPR: Implications for Virulence Regulation and Application to Vaccine Development
title_full_unstemmed	Evolutionary Landscape of the <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Complex from the Viewpoint of PhoPR: Implications for Virulence Regulation and Application to Vaccine Development
title_sort	evolutionary landscape of the <named-content content-type="genus-species">mycobacterium tuberculosis</named-content> complex from the viewpoint of phopr: implications for virulence regulation and application to vaccine development
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/dc68ad2f42ef426fa0c0e7ef283f2033
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Evolutionary Landscape of the <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Complex from the Viewpoint of PhoPR: Implications for Virulence Regulation and Application to Vaccine Development

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