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Streptococcus pyogenes Hijacks Host Glutathione for Growth and Innate Immune Evasion

Brouwer, Stephan; Jespersen, Magnus G.; Ong, Cheryl-lynn Y.; De Oliveira, David M.P.; Keller, Bernhard; Cork, Amanda J.; Djoko, Karrera Y.; Davies, Mark R.; Walker, Mark J.

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Authors

Stephan Brouwer

Magnus G. Jespersen

Cheryl-lynn Y. Ong

David M.P. De Oliveira

Bernhard Keller

Amanda J. Cork

Mark R. Davies

Mark J. Walker



Abstract

The nasopharynx and the skin are the major oxygen-rich anatomical sites for colonization by the human pathogen Streptococcus pyogenes (group A Streptococcus [GAS]). To establish infection, GAS must survive oxidative stress generated during aerobic metabolism and the release of reactive oxygen species (ROS) by host innate immune cells. Glutathione is the major host antioxidant molecule, while GAS is glutathione auxotrophic. Here, we report the molecular characterization of the ABC transporter substrate binding protein GshT in the GAS glutathione salvage pathway. We demonstrate that glutathione uptake is critical for aerobic growth of GAS and that impaired import of glutathione induces oxidative stress that triggers enhanced production of the reducing equivalent NADPH. Our results highlight the interrelationship between glutathione assimilation, carbohydrate metabolism, virulence factor production, and innate immune evasion. Together, these findings suggest an adaptive strategy employed by extracellular bacterial pathogens to exploit host glutathione stores for their own benefit. IMPORTANCE During infection, microbes must escape host immune responses and survive exposure to reactive oxygen species produced by immune cells. Here, we identify the ABC transporter substrate binding protein GshT as a key component of the glutathione salvage pathway in glutathione-auxotrophic GAS. Host-acquired glutathione is crucial to the GAS antioxidant defense system, facilitating escape from the host innate immune response. This study demonstrates a direct link between glutathione assimilation, aerobic metabolism, and virulence factor production in an important human pathogen. Our findings provide mechanistic insight into host adaptation that enables extracellular bacterial pathogens such as GAS to exploit the abundance of glutathione in the host cytosol for their own benefit.

Citation

Brouwer, S., Jespersen, M. G., Ong, C. Y., De Oliveira, D. M., Keller, B., Cork, A. J., …Walker, M. J. (2022). Streptococcus pyogenes Hijacks Host Glutathione for Growth and Innate Immune Evasion. mBio, 13(3), https://doi.org/10.1128/mbio.00676-22

Journal Article Type Article
Acceptance Date Mar 18, 2022
Online Publication Date Apr 25, 2022
Publication Date 2022-06
Deposit Date Jun 27, 2022
Publicly Available Date Jun 27, 2022
Journal mBio
Print ISSN 2161-2129
Publisher American Society for Microbiology
Peer Reviewed Peer Reviewed
Volume 13
Issue 3
DOI https://doi.org/10.1128/mbio.00676-22

Files

Published Journal Article (Advance Online Version) (1.9 Mb)
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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
Advance Online Version © 2022 Brouwer et al. This is an
open-access article distributed under the terms
of the Creative Commons Attribution 4.0
International license







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