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Article Dans Une Revue PLoS Pathogens Année : 2022

Inhibition of the master regulator of Listeria monocytogenes virulence enables bacterial clearance from spacious replication vacuoles in infected macrophages

Thao Thanh Tran (1) , Carmen D Mathmann (1) , Marcela Gatica-Andrades (1) , Rachel F Rollo (1) , Melanie Oelker (2) , Johanna K Ljungberg (1) , Tam T K Nguyen (1) , Alina Zamoshnikova (1) , Lalith K Kummari (3, 4) , Orry J K Wyer (1) , Katharine M Irvine (4, 5) , Javier Melo-Bolívar (1) , Annette Gross (1) , Darren Brown (4) , Jeffrey y W Mak (4, 5) , David P Fairlie (4, 5) , Karl A Hansford (4) , Matthew A Cooper (4) , Rabina Giri (6) , Veronika Schreiber (6) , Shannon R Joseph (7) , Fiona Simpson (7) , Timothy C Barnett (8) , Jörgen Johansson (9) , Wendy Dankers (10) , James Harris (10) , Timothy J Wells (11) , Ronan Kapetanovic (4) , Matthew J Sweet (4) , Eleanor A Latomanski (12) , Hayley J Newton (12) , Romain J R Guérillot (12) , Abderrahman Hachani (12) , Timothy P Stinear (12) , Sze Ying Ong (12, 13) , Yogeswari Chandran (13, 12) , Elizabeth L Hartland (12, 13) , Bostjan Kobe (14, 4) , Jennifer L Stow (4) , A. Elisabeth Sauer-Eriksson (2) , Jakob Begun (15) , Jessica C Kling (7) , Antje Blumenthal (7)
1 University of Queensland - The Diamantina Institute
2 Department of Chemistry, Umeå University, 90187, Umeå, Sweden
3 School of Chemistry and Molecular Biosciences, Australian Infectious Diseases Research Centre
4 Institute for Molecular Bioscience
5 Australian Research Council Centre of Excellence in Advanced Molecular Imaging [Victoria, Australia]
6 Mater Research Institute - The University of Queensland, Brisbane, Australia
7 The University of Queensland Diamantina Institute, Brisbane, Australia
8 Wesfarmers Centre for Vaccines and Infectious Diseases
9 Umeå University, Sweden
10 School of Clinical Sciences at Monash Health
11 The University of Queensland Diamantina Institute, Brisbane, Australia.
12 The Peter Doherty Institute for Infection and Immunity [Melbourne]
13 Hudson Institute of Medical Research and Department of Molecular and Translational Science
14 School of Chemistry and Molecular Biosciences
15 Mater Research Institute - The University of Queensland,
Thao Thanh Tran
  • Fonction : Auteur
University of Queensland - The Diamantina Institute
Carmen D Mathmann
University of Queensland - The Diamantina Institute
Marcela Gatica-Andrades
  • Fonction : Auteur
University of Queensland - The Diamantina Institute
Rachel F Rollo
University of Queensland - The Diamantina Institute
Melanie Oelker
  • Fonction : Auteur
Department of Chemistry, Umeå University, 90187, Umeå, Sweden
Johanna K Ljungberg
  • Fonction : Auteur
University of Queensland - The Diamantina Institute
Tam T K Nguyen
  • Fonction : Auteur
University of Queensland - The Diamantina Institute
Alina Zamoshnikova
University of Queensland - The Diamantina Institute
Lalith K Kummari
School of Chemistry and Molecular Biosciences, Australian Infectious Diseases Research Centre
Institute for Molecular Bioscience
Orry J K Wyer
  • Fonction : Auteur
University of Queensland - The Diamantina Institute
Katharine M Irvine
Institute for Molecular Bioscience
Australian Research Council Centre of Excellence in Advanced Molecular Imaging [Victoria, Australia]
Javier Melo-Bolívar
University of Queensland - The Diamantina Institute
Annette Gross
University of Queensland - The Diamantina Institute
Darren Brown
Institute for Molecular Bioscience
Jeffrey y W Mak
Institute for Molecular Bioscience
Australian Research Council Centre of Excellence in Advanced Molecular Imaging [Victoria, Australia]
David P Fairlie
  • Fonction : Auteur
Institute for Molecular Bioscience
Australian Research Council Centre of Excellence in Advanced Molecular Imaging [Victoria, Australia]
Karl A Hansford
Institute for Molecular Bioscience
Matthew A Cooper
Institute for Molecular Bioscience
Rabina Giri
Mater Research Institute - The University of Queensland, Brisbane, Australia
Veronika Schreiber
  • Fonction : Auteur
Mater Research Institute - The University of Queensland, Brisbane, Australia
Shannon R Joseph
  • Fonction : Auteur
The University of Queensland Diamantina Institute, Brisbane, Australia
Fiona Simpson
The University of Queensland Diamantina Institute, Brisbane, Australia
Timothy C Barnett
Wesfarmers Centre for Vaccines and Infectious Diseases
Jörgen Johansson
  • Fonction : Auteur
Umeå University, Sweden
Wendy Dankers
School of Clinical Sciences at Monash Health
James Harris
School of Clinical Sciences at Monash Health
Timothy J Wells
The University of Queensland Diamantina Institute, Brisbane, Australia.
Ronan Kapetanovic
Institute for Molecular Bioscience
CV
Matthew J Sweet
Institute for Molecular Bioscience
Eleanor A Latomanski
  • Fonction : Auteur
The Peter Doherty Institute for Infection and Immunity [Melbourne]
Hayley J Newton
The Peter Doherty Institute for Infection and Immunity [Melbourne]
Romain J R Guérillot
The Peter Doherty Institute for Infection and Immunity [Melbourne]
Abderrahman Hachani
The Peter Doherty Institute for Infection and Immunity [Melbourne]
Timothy P Stinear
The Peter Doherty Institute for Infection and Immunity [Melbourne]
Sze Ying Ong
  • Fonction : Auteur
The Peter Doherty Institute for Infection and Immunity [Melbourne]
Hudson Institute of Medical Research and Department of Molecular and Translational Science
Yogeswari Chandran
Hudson Institute of Medical Research and Department of Molecular and Translational Science
The Peter Doherty Institute for Infection and Immunity [Melbourne]
Elizabeth L Hartland
The Peter Doherty Institute for Infection and Immunity [Melbourne]
Hudson Institute of Medical Research and Department of Molecular and Translational Science
Bostjan Kobe
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience
Jennifer L Stow
  • Fonction : Auteur
Institute for Molecular Bioscience
A. Elisabeth Sauer-Eriksson
  • Fonction : Auteur
Department of Chemistry, Umeå University, 90187, Umeå, Sweden
Jakob Begun
Mater Research Institute - The University of Queensland,
Jessica C Kling
  • Fonction : Auteur
The University of Queensland Diamantina Institute, Brisbane, Australia
Antje Blumenthal
The University of Queensland Diamantina Institute, Brisbane, Australia

Résumé

A hallmark of Listeria (L.) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L. monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L. monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria-containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L. monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L. monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L. monocytogenes in macrophages is not inevitably tied to bacterial persistence.

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Immunologie
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Soumis le : mercredi 22 novembre 2023-15:38:34

Dernière modification le : mardi 30 avril 2024-15:10:03

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hal-04300400 , version 1 (22-11-2023)

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Thao Thanh Tran, Carmen D Mathmann, Marcela Gatica-Andrades, Rachel F Rollo, Melanie Oelker, et al.. Inhibition of the master regulator of Listeria monocytogenes virulence enables bacterial clearance from spacious replication vacuoles in infected macrophages. PLoS Pathogens, 2022, 18 (1), pp.e1010166. ⟨10.1371/journal.ppat.1010166⟩. ⟨hal-04300400⟩

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