A Nonribosomal Peptide Synthase Gene Driving Virulence in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

ABSTRACT Nonribosomal peptide synthases produce short peptides in a manner that is distinct from classical mRNA-dependent ribosome-mediated translation. The Mycobacterium tuberculosis genome harbors a nonribosomal peptide synthase gene, nrp, which is part of a gene cluster proposed to be involved in...

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Autores principales:	Kiranmai Bhatt, Henrique Machado, Nuno S. Osório, Jeremy Sousa, Filipa Cardoso, Carlos Magalhães, Bing Chen, Mei Chen, John Kim, Albel Singh, Catarina M. Ferreira, António G. Castro, Egidio Torrado, William R. Jacobs, Apoorva Bhatt, Margarida Saraiva
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	immune deficiency pathogenesis tuberculosis virulence factors Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1ca69f777d56487ab7f418ab4f795bf6
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spelling	oai:doaj.org-article:1ca69f777d56487ab7f418ab4f795bf62021-11-15T15:22:26ZA Nonribosomal Peptide Synthase Gene Driving Virulence in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>10.1128/mSphere.00352-182379-5042https://doaj.org/article/1ca69f777d56487ab7f418ab4f795bf62018-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00352-18https://doaj.org/toc/2379-5042ABSTRACT Nonribosomal peptide synthases produce short peptides in a manner that is distinct from classical mRNA-dependent ribosome-mediated translation. The Mycobacterium tuberculosis genome harbors a nonribosomal peptide synthase gene, nrp, which is part of a gene cluster proposed to be involved in the biosynthesis of isonitrile lipopeptides. Orthologous clusters are found in other slow-growing pathogenic mycobacteria and actinomycetes. To probe the role of the nrp gene in infection, we generated an nrp deletion mutant in M. tuberculosis H37Rv and tested its virulence in immunocompetent (C57BL/6) mice. The nrp mutant strain displayed lower initial growth rates in the lungs and a defective dissemination to the spleens of infected mice. Mice infected with the mutant strain also survived for twice as long as those infected with wild-type M. tuberculosis and, remarkably, showed subdued pathology, despite similar bacterial loads at later stages of infection. The differences in the course of infection between wild-type and nrp mutant strains were accompanied by distinct dynamics of the immune response. Most strikingly, the nrp mutant was highly attenuated in immunodeficient (SCID-, recombination activating 2 [RAG2]-, and gamma interferon [IFN-γ]-deficient) mice, suggesting that macrophages control the nrp mutant more efficiently than they control the wild-type strain. However, in the presence of IFN-γ, both strains were equally controlled. We propose that the nrp gene and its associated cluster are drivers of virulence during the early stages of infection. IMPORTANCE Over 10 million people developed tuberculosis (TB) in 2016, and over 1.8 million individuals succumbed to the disease. These numbers make TB the ninth leading cause of death worldwide and the leading cause from a single infectious agent. Therefore, finding novel therapeutic targets in Mycobacterium tuberculosis, the pathogen that causes most cases of human TB, is critical. In this study, we reveal a novel virulence factor in M. tuberculosis, the nrp gene. The lack of nrp highly attenuates the course of M. tuberculosis infection in the mouse model, which is particularly relevant in immune-deficient hosts. This is very relevant as TB is particularly incident in immune-suppressed individuals, such as HIV patients.Kiranmai BhattHenrique MachadoNuno S. OsórioJeremy SousaFilipa CardosoCarlos MagalhãesBing ChenMei ChenJohn KimAlbel SinghCatarina M. FerreiraAntónio G. CastroEgidio TorradoWilliam R. JacobsApoorva BhattMargarida SaraivaAmerican Society for Microbiologyarticleimmune deficiencypathogenesistuberculosisvirulence factorsMicrobiologyQR1-502ENmSphere, Vol 3, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	immune deficiency pathogenesis tuberculosis virulence factors Microbiology QR1-502
spellingShingle	immune deficiency pathogenesis tuberculosis virulence factors Microbiology QR1-502 Kiranmai Bhatt Henrique Machado Nuno S. Osório Jeremy Sousa Filipa Cardoso Carlos Magalhães Bing Chen Mei Chen John Kim Albel Singh Catarina M. Ferreira António G. Castro Egidio Torrado William R. Jacobs Apoorva Bhatt Margarida Saraiva A Nonribosomal Peptide Synthase Gene Driving Virulence in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
description	ABSTRACT Nonribosomal peptide synthases produce short peptides in a manner that is distinct from classical mRNA-dependent ribosome-mediated translation. The Mycobacterium tuberculosis genome harbors a nonribosomal peptide synthase gene, nrp, which is part of a gene cluster proposed to be involved in the biosynthesis of isonitrile lipopeptides. Orthologous clusters are found in other slow-growing pathogenic mycobacteria and actinomycetes. To probe the role of the nrp gene in infection, we generated an nrp deletion mutant in M. tuberculosis H37Rv and tested its virulence in immunocompetent (C57BL/6) mice. The nrp mutant strain displayed lower initial growth rates in the lungs and a defective dissemination to the spleens of infected mice. Mice infected with the mutant strain also survived for twice as long as those infected with wild-type M. tuberculosis and, remarkably, showed subdued pathology, despite similar bacterial loads at later stages of infection. The differences in the course of infection between wild-type and nrp mutant strains were accompanied by distinct dynamics of the immune response. Most strikingly, the nrp mutant was highly attenuated in immunodeficient (SCID-, recombination activating 2 [RAG2]-, and gamma interferon [IFN-γ]-deficient) mice, suggesting that macrophages control the nrp mutant more efficiently than they control the wild-type strain. However, in the presence of IFN-γ, both strains were equally controlled. We propose that the nrp gene and its associated cluster are drivers of virulence during the early stages of infection. IMPORTANCE Over 10 million people developed tuberculosis (TB) in 2016, and over 1.8 million individuals succumbed to the disease. These numbers make TB the ninth leading cause of death worldwide and the leading cause from a single infectious agent. Therefore, finding novel therapeutic targets in Mycobacterium tuberculosis, the pathogen that causes most cases of human TB, is critical. In this study, we reveal a novel virulence factor in M. tuberculosis, the nrp gene. The lack of nrp highly attenuates the course of M. tuberculosis infection in the mouse model, which is particularly relevant in immune-deficient hosts. This is very relevant as TB is particularly incident in immune-suppressed individuals, such as HIV patients.
format	article
author	Kiranmai Bhatt Henrique Machado Nuno S. Osório Jeremy Sousa Filipa Cardoso Carlos Magalhães Bing Chen Mei Chen John Kim Albel Singh Catarina M. Ferreira António G. Castro Egidio Torrado William R. Jacobs Apoorva Bhatt Margarida Saraiva
author_facet	Kiranmai Bhatt Henrique Machado Nuno S. Osório Jeremy Sousa Filipa Cardoso Carlos Magalhães Bing Chen Mei Chen John Kim Albel Singh Catarina M. Ferreira António G. Castro Egidio Torrado William R. Jacobs Apoorva Bhatt Margarida Saraiva
author_sort	Kiranmai Bhatt
title	A Nonribosomal Peptide Synthase Gene Driving Virulence in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_short	A Nonribosomal Peptide Synthase Gene Driving Virulence in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full	A Nonribosomal Peptide Synthase Gene Driving Virulence in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_fullStr	A Nonribosomal Peptide Synthase Gene Driving Virulence in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full_unstemmed	A Nonribosomal Peptide Synthase Gene Driving Virulence in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_sort	nonribosomal peptide synthase gene driving virulence in <named-content content-type="genus-species">mycobacterium tuberculosis</named-content>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/1ca69f777d56487ab7f418ab4f795bf6
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A Nonribosomal Peptide Synthase Gene Driving Virulence in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

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