Mutations in ppe38 block PE_PGRS secretion and increase virulence of Mycobacterium tuberculosis

Handle URI:
http://hdl.handle.net/10754/626974
Title:
Mutations in ppe38 block PE_PGRS secretion and increase virulence of Mycobacterium tuberculosis
Authors:
Ates, Louis S. ( 0000-0002-2953-8010 ) ; Dippenaar, Anzaan; Ummels, Roy; Piersma, Sander R.; van der Woude, Aniek D.; van der Kuij, Kim; Le Chevalier, Fabien; Mata-Espinosa, Dulce; Barrios-Payán, Jorge; Marquina-Castillo, Brenda; Guapillo, Carolina; Jiménez, Connie R.; Pain, Arnab ( 0000-0002-1755-2819 ) ; Houben, Edith N. G.; Warren, Robin M.; Brosch, Roland ( 0000-0003-2587-3863 ) ; Hernández-Pando, Rogelio; Bitter, Wilbert ( 0000-0001-8347-6511 )
Abstract:
Mycobacterium tuberculosis requires a large number of secreted and exported proteins for its virulence, immune modulation and nutrient uptake. Most of these proteins are transported by the different type VII secretion systems1,2. The most recently evolved type VII secretion system, ESX-5, secretes dozens of substrates belonging to the PE and PPE families, which are named for conserved proline and glutamic acid residues close to the amino terminus3,4. However, the role of these proteins remains largely elusive1. Here, we show that mutations of ppe38 completely block the secretion of two large subsets of ESX-5 substrates, that is, PPE-MPTR and PE_PGRS, together comprising >80 proteins. Importantly, hypervirulent clinical M. tuberculosis strains of the Beijing lineage have such a mutation and a concomitant loss of secretion5. Restoration of PPE38-dependent secretion partially reverted the hypervirulence phenotype of a Beijing strain, and deletion of ppe38 in moderately virulent M. tuberculosis increased virulence. This indicates that these ESX-5 substrates have an important role in virulence attenuation. Phylogenetic analysis revealed that deletion of ppe38 occurred at the branching point of the ‘modern’ Beijing sublineage and is shared by Beijing outbreak strains worldwide, suggesting that this deletion may have contributed to their success and global distribution6,7.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program; Pathogen Genomics Laboratory
Citation:
Ates LS, Dippenaar A, Ummels R, Piersma SR, van der Woude AD, et al. (2018) Mutations in ppe38 block PE_PGRS secretion and increase virulence of Mycobacterium tuberculosis. Nature Microbiology 3: 181–188. Available: http://dx.doi.org/10.1038/s41564-017-0090-6.
Publisher:
Springer Nature
Journal:
Nature Microbiology
KAUST Grant Number:
BAS/1/1020-01-01
Issue Date:
12-Jan-2018
DOI:
10.1038/s41564-017-0090-6
Type:
Article
ISSN:
2058-5276
Sponsors:
We thank N. C. Gey van Pittius, B. Appelmelk, J. Luirink and A. van der Sar for useful discussions and help with data interpretation. We also thank M. Sparrius, V. van Winden, R. Simeone and M. Kok for technical assistance. Furthermore we thank members of the Pathogen Genomics group and the Bioscience Core laboratory in King Abdullah University of Science and Technology (KAUST) for generating the sequencing data on the M. tuberculosis isolates described in the study. We also thank T. Phan for LC-MS/MS data analysis. E.N.G.H. was funded by a VIDI grant from the Netherlands Organization of Scientific Research. R.H.-P. was funded by grant CONACyT contract FC 2015-/115 and IMMUNOCANEI grant 253053. A.P. is funded by a faculty baseline funding (BAS/1/1020-01-01) by KAUST. L.S.A., F.L.C. and R.B. acknowledge support by grants ANR-14-JAMR-001-02 and ANR-10-LABX-62-IBEID and the European Union’s Horizon 2020 Research and Innovation Program grant 643381. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Additional Links:
https://www.nature.com/articles/s41564-017-0090-6
Appears in Collections:
Articles; Bioscience Program; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorAtes, Louis S.en
dc.contributor.authorDippenaar, Anzaanen
dc.contributor.authorUmmels, Royen
dc.contributor.authorPiersma, Sander R.en
dc.contributor.authorvan der Woude, Aniek D.en
dc.contributor.authorvan der Kuij, Kimen
dc.contributor.authorLe Chevalier, Fabienen
dc.contributor.authorMata-Espinosa, Dulceen
dc.contributor.authorBarrios-Payán, Jorgeen
dc.contributor.authorMarquina-Castillo, Brendaen
dc.contributor.authorGuapillo, Carolinaen
dc.contributor.authorJiménez, Connie R.en
dc.contributor.authorPain, Arnaben
dc.contributor.authorHouben, Edith N. G.en
dc.contributor.authorWarren, Robin M.en
dc.contributor.authorBrosch, Rolanden
dc.contributor.authorHernández-Pando, Rogelioen
dc.contributor.authorBitter, Wilberten
dc.date.accessioned2018-02-01T07:25:00Z-
dc.date.available2018-02-01T07:25:00Z-
dc.date.issued2018-01-12en
dc.identifier.citationAtes LS, Dippenaar A, Ummels R, Piersma SR, van der Woude AD, et al. (2018) Mutations in ppe38 block PE_PGRS secretion and increase virulence of Mycobacterium tuberculosis. Nature Microbiology 3: 181–188. Available: http://dx.doi.org/10.1038/s41564-017-0090-6.en
dc.identifier.issn2058-5276en
dc.identifier.doi10.1038/s41564-017-0090-6en
dc.identifier.urihttp://hdl.handle.net/10754/626974-
dc.description.abstractMycobacterium tuberculosis requires a large number of secreted and exported proteins for its virulence, immune modulation and nutrient uptake. Most of these proteins are transported by the different type VII secretion systems1,2. The most recently evolved type VII secretion system, ESX-5, secretes dozens of substrates belonging to the PE and PPE families, which are named for conserved proline and glutamic acid residues close to the amino terminus3,4. However, the role of these proteins remains largely elusive1. Here, we show that mutations of ppe38 completely block the secretion of two large subsets of ESX-5 substrates, that is, PPE-MPTR and PE_PGRS, together comprising >80 proteins. Importantly, hypervirulent clinical M. tuberculosis strains of the Beijing lineage have such a mutation and a concomitant loss of secretion5. Restoration of PPE38-dependent secretion partially reverted the hypervirulence phenotype of a Beijing strain, and deletion of ppe38 in moderately virulent M. tuberculosis increased virulence. This indicates that these ESX-5 substrates have an important role in virulence attenuation. Phylogenetic analysis revealed that deletion of ppe38 occurred at the branching point of the ‘modern’ Beijing sublineage and is shared by Beijing outbreak strains worldwide, suggesting that this deletion may have contributed to their success and global distribution6,7.en
dc.description.sponsorshipWe thank N. C. Gey van Pittius, B. Appelmelk, J. Luirink and A. van der Sar for useful discussions and help with data interpretation. We also thank M. Sparrius, V. van Winden, R. Simeone and M. Kok for technical assistance. Furthermore we thank members of the Pathogen Genomics group and the Bioscience Core laboratory in King Abdullah University of Science and Technology (KAUST) for generating the sequencing data on the M. tuberculosis isolates described in the study. We also thank T. Phan for LC-MS/MS data analysis. E.N.G.H. was funded by a VIDI grant from the Netherlands Organization of Scientific Research. R.H.-P. was funded by grant CONACyT contract FC 2015-/115 and IMMUNOCANEI grant 253053. A.P. is funded by a faculty baseline funding (BAS/1/1020-01-01) by KAUST. L.S.A., F.L.C. and R.B. acknowledge support by grants ANR-14-JAMR-001-02 and ANR-10-LABX-62-IBEID and the European Union’s Horizon 2020 Research and Innovation Program grant 643381. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.en
dc.publisherSpringer Natureen
dc.relation.urlhttps://www.nature.com/articles/s41564-017-0090-6en
dc.titleMutations in ppe38 block PE_PGRS secretion and increase virulence of Mycobacterium tuberculosisen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentBioscience Programen
dc.contributor.departmentPathogen Genomics Laboratoryen
dc.identifier.journalNature Microbiologyen
dc.contributor.institutionUnit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, Paris, Franceen
dc.contributor.institutionDepartment of Medical Microbiology and Infection Prevention, VU University Medical Center, Amsterdam, The Netherlandsen
dc.contributor.institutionDST/NRF Centre of Excellence for Biomedical Tuberculosis Research, SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africaen
dc.contributor.institutionDepartment of Medical Oncology, OncoProteomics Laboratory, VU University Medical Center, Amsterdam, Netherlandsen
dc.contributor.institutionExperimental Pathology Section, Department of Pathology, National Institute of Medical Sciences and Nutrition “Salvador Zubirán”, México City, Mexicoen
dc.contributor.institutionSection Molecular Microbiology, Amsterdam Institute of Molecules, Medicine & Systems, Vrije Universiteit, Amsterdam, The Netherlandsen
kaust.authorPain, Arnaben
kaust.grant.numberBAS/1/1020-01-01en
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