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Microscopy-based phenotypic profiling of infection by Staphylococcus aureus clinical isolates reveals intracellular lifestyle as a prevalent feature

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Ines Rodrigues Lopes, Laura Maria Alcantara, Ricardo Jorge Silva, Jerome Josse, Elena Pedrero Vega, Ana Marina Cabrerizo, Melanie Bonhomme, Daniel Lopez, Frederic Laurent, Francois Vandenesch, Miguel Mano, Ana Eulalio

Original languageEnglish
Article number7174
JournalNature Communications
Volume13
Issue number1
Early online date22 Nov 2022
DOIs
Accepted/In press8 Nov 2022
E-pub ahead of print22 Nov 2022
PublishedDec 2022

Bibliographical note

Funding Information: I.R.L. and R.J.S. are recipients of PhD fellowships (PD/BD/146464/2019 and PD/BD/129294/2017) of the Doctoral Program in Experimental Biology and Biomedicine of the Center for Neuroscience and Cell Biology, University of Coimbra. We thank Martin J. Fraunholz (University of Würzburg) for providing the pLVTHM-H2B-BFP-IRES-mRFP-CWT plasmid, and Ian Monk (University of Melbourne, Australia) for the E. coli IM08B and IM01B strains. This work was supported by grants from the European Union’s Horizon 2020 research and innovation program (under the Marie Skłodowska-Curie grant agreement No 893942 to L.M.A), ERA-NET Infect-ERA StaphIN (031L0094, BMBF, Germany, to A.E.; Infect-ERA/0001/2015, FCT, Portugal, to M.M.; PCIN-2015-151, MINECO, Spain, to D.L.; and ANR 15-IFEC-0002-04, France, to F.L. and F.V), and the ERDF—European Regional Development Fund through COMPETE 2020 and Portuguese Foundation for Science and Technology (POCI-01-0145-FEDER-007440, UIDB/04539/2020, POCI-01-0145-FEDER-029999 to M.M. and A.E.). Funding Information: I.R.L. and R.J.S. are recipients of PhD fellowships (PD/BD/146464/2019 and PD/BD/129294/2017) of the Doctoral Program in Experimental Biology and Biomedicine of the Center for Neuroscience and Cell Biology, University of Coimbra. We thank Martin J. Fraunholz (University of Würzburg) for providing the pLVTHM-H2B-BFP-IRES-mRFP-CWT plasmid, and Ian Monk (University of Melbourne, Australia) for the E. coli IM08B and IM01B strains. This work was supported by grants from the European Union’s Horizon 2020 research and innovation program (under the Marie Skłodowska-Curie grant agreement No 893942 to L.M.A), ERA-NET Infect-ERA StaphIN (031L0094, BMBF, Germany, to A.E.; Infect-ERA/0001/2015, FCT, Portugal, to M.M.; PCIN-2015-151, MINECO, Spain, to D.L.; and ANR 15-IFEC-0002-04, France, to F.L. and F.V), and the ERDF—European Regional Development Fund through COMPETE 2020 and Portuguese Foundation for Science and Technology (POCI-01-0145-FEDER-007440, UIDB/04539/2020, POCI-01-0145-FEDER-029999 to M.M. and A.E.). Publisher Copyright: © 2022, The Author(s).

King's Authors

Abstract

Staphylococcus aureus is increasingly recognized as a facultative intracellular pathogen, although the significance and pervasiveness of its intracellular lifestyle remain controversial. Here, we applied fluorescence microscopy-based infection assays and automated image analysis to profile the interaction of 191 S. aureus isolates from patients with bone/joint infections, bacteremia, and infective endocarditis, with four host cell types, at five times post-infection. This multiparametric analysis revealed that almost all isolates are internalized and that a large fraction replicate and persist within host cells, presenting distinct infection profiles in non-professional vs. professional phagocytes. Phenotypic clustering highlighted interesting sub-groups, including one comprising isolates exhibiting high intracellular replication and inducing delayed host death in vitro and in vivo. These isolates are deficient for the cysteine protease staphopain A. This study establishes S. aureus intracellular lifestyle as a prevalent feature of infection, with potential implications for the effective treatment of staphylococcal infections.

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