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

Louis S. Ates, Anzaan Dippenaar, Roy Ummels, Sander R. Piersma, Aniek D. van der Woude, Kim van der Kuij, Fabien Le Chevalier, Dulce Mata-Espinosa, Jorge Barrios-Payán, Brenda Marquina-Castillo, Carolina Guapillo, Connie R. Jiménez, Arnab Pain, Edith N. G. Houben, Robin M. Warren, Roland Brosch, Rogelio Hernández-Pando, Wilbert Bitter

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

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.
Original languageEnglish (US)
Pages (from-to)181-188
Number of pages8
JournalNature Microbiology
Volume3
Issue number2
DOIs
StatePublished - Jan 15 2018

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledged KAUST grant number(s): BAS/1/1020-01-01
Acknowledgements: 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.

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