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

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    Type
    Article
    Authors
    Ates, Louis S. cc
    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 cc
    Houben, Edith N. G.
    Warren, Robin M.
    Brosch, Roland cc
    Hernández-Pando, Rogelio
    Bitter, Wilbert cc
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Pathogen Genomics Laboratory
    KAUST Grant Number
    BAS/1/1020-01-01
    Date
    2018-01-15
    Online Publication Date
    2018-01-15
    Print Publication Date
    2018-02
    Permanent link to this record
    http://hdl.handle.net/10754/626974
    
    Metadata
    Show full item record
    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.
    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.
    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.
    Publisher
    Springer Nature
    Journal
    Nature Microbiology
    DOI
    10.1038/s41564-017-0090-6
    PubMed ID
    29335553
    Additional Links
    https://www.nature.com/articles/s41564-017-0090-6
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41564-017-0090-6
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program

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