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 journalArticleAcademicpeer-review

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 systems 1,2 . 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 terminus 3,4 . However, the role of these proteins remains largely elusive 1 . 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 secretion 5 . 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 distribution 6,7 .
Original languageEnglish
Pages (from-to)181-188
JournalNature Microbiology
Volume3
Issue number2
DOIs
Publication statusPublished - 2018

Cite this

Ates, Louis S. ; 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 ; Houben, Edith N. G. ; Warren, Robin M. ; Brosch, Roland ; Hernández-Pando, Rogelio ; Bitter, Wilbert. / Mutations in ppe38 block PE-PGRS secretion and increase virulence of Mycobacterium tuberculosis. In: Nature Microbiology. 2018 ; Vol. 3, No. 2. pp. 181-188.
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title = "Mutations in ppe38 block PE-PGRS secretion and increase virulence of Mycobacterium tuberculosis",
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 systems 1,2 . 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 terminus 3,4 . However, the role of these proteins remains largely elusive 1 . 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 secretion 5 . 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 distribution 6,7 .",
author = "Ates, {Louis S.} and Anzaan Dippenaar and Roy Ummels and Piersma, {Sander R.} and {van der Woude}, {Aniek D.} and {van der Kuij}, Kim and {le Chevalier}, Fabien and Dulce Mata-Espinosa and Jorge Barrios-Pay{\'a}n and Brenda Marquina-Castillo and Carolina Guapillo and Jim{\'e}nez, {Connie R.} and Arnab Pain and Houben, {Edith N. G.} and Warren, {Robin M.} and Roland Brosch and Rogelio Hern{\'a}ndez-Pando and Wilbert Bitter",
year = "2018",
doi = "10.1038/s41564-017-0090-6",
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Ates, LS, Dippenaar, A, Ummels, R, Piersma, SR, van der Woude, AD, van der Kuij, K, le Chevalier, F, Mata-Espinosa, D, Barrios-Payán, J, Marquina-Castillo, B, Guapillo, C, Jiménez, CR, Pain, A, Houben, ENG, Warren, RM, Brosch, R, Hernández-Pando, R & Bitter, W 2018, 'Mutations in ppe38 block PE-PGRS secretion and increase virulence of Mycobacterium tuberculosis' Nature Microbiology, vol. 3, no. 2, pp. 181-188. https://doi.org/10.1038/s41564-017-0090-6

Mutations in ppe38 block PE-PGRS secretion and increase virulence of Mycobacterium tuberculosis. / Ates, Louis S.; 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; Houben, Edith N. G.; Warren, Robin M.; Brosch, Roland; Hernández-Pando, Rogelio; Bitter, Wilbert.

In: Nature Microbiology, Vol. 3, No. 2, 2018, p. 181-188.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Mutations in ppe38 block PE-PGRS secretion and increase virulence of Mycobacterium tuberculosis

AU - Ates, Louis S.

AU - Dippenaar, Anzaan

AU - Ummels, Roy

AU - Piersma, Sander R.

AU - van der Woude, Aniek D.

AU - van der Kuij, Kim

AU - le Chevalier, Fabien

AU - Mata-Espinosa, Dulce

AU - Barrios-Payán, Jorge

AU - Marquina-Castillo, Brenda

AU - Guapillo, Carolina

AU - Jiménez, Connie R.

AU - Pain, Arnab

AU - Houben, Edith N. G.

AU - Warren, Robin M.

AU - Brosch, Roland

AU - Hernández-Pando, Rogelio

AU - Bitter, Wilbert

PY - 2018

Y1 - 2018

N2 - 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 systems 1,2 . 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 terminus 3,4 . However, the role of these proteins remains largely elusive 1 . 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 secretion 5 . 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 distribution 6,7 .

AB - 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 systems 1,2 . 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 terminus 3,4 . However, the role of these proteins remains largely elusive 1 . 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 secretion 5 . 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 distribution 6,7 .

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